Salsa 2

CHAPTER
4
Gastrointestinal Hormones
and Neurotransmitters
DIEGO V. BOHÓRQUEZ AND RODGER A. LIDDLE
CHAPTER OUTLINE
Hormones and Neurotransmitters................................................36 The Transmitters.........................................................................42
Definitions................................................................................... 36 Gut Neuropeptides...................................................................... 43
Modes of Transmitter Release..................................................... 37 Neurotransmitters........................................................................ 47
Transducing Signals from the Gastrointestinal Lumen.................38 Cannabinoids and Other Chemical Transmitters............................ 49
Recognizing Signals Through Cell Surface Receptors.................... 40 The Importance of Hormones and Neurotransmitters..................50
Nutrient Chemosensing............................................................... 41 Growth and Abnormal Growth of the Gastrointestinal Mucosa....... 50
Sensing the Microbiome.............................................................. 42 Diabetes Mellitus and the Gastrointestinal Tract........................... 52
Other Factors That Stimulate Transmitter Release........................ 42 Gastrointestinal Regulation of Appetite......................................... 53
The GI tract relies on hormones and neurotransmitters to inte- hormone-containing cells of the GI tract has been questioned,
grate signals arising in the lumen with whole-body homeosta- and it becomes important to distinguish hormonal from neu-
sis. As an example, satiety in the brain is to a great extent ronal actions.
induced by the presence of food in the gut. This process begins
with ingestion of nutrients that stimulate sensory cells in the
intestinal epithelium that modulate food intake via the release
Definitions
of specific chemical messengers. GI hormones and neurotrans- Established criteria exist for determining whether a candidate
mitters are intimately involved with every aspect of the diges- transmitter is a true hormone or a neurotransmitter. The first
tive process, including ingestion and absorption of nutrients, hormone to be discovered was secretin, when it was shown
so it is not surprising that these transmitters are essential for that injection of intestinal extracts into the blood stimulated
life.1,2 In this chapter, the critical role of the regulatory trans- pancreatic secretion.3 Since then the following criteria have
mitters in GI function is analyzed by covering the following been established to prove that a substance functions as a
aspects: their synthesis and secretion from sensory epithelial hormone. First, the stimulation of one organ must cause a
cells, how food or other GI luminal factors trigger their release, distant response by acting through the blood. Second, the
the most representative members, and their importance in the response must be independent of neural stimulation. Third, no
context of disease. response should occur in the absence of the secretory organ.
And fourth, the response should be reproducible by applying
pure amounts of the candidate hormone onto the target tissue.
HORMONES AND NEUROTRANSMITTERS There are over 30 GI hormones that meet these criteria, and
their singularities are discussed in “The Transmitters” section
The sensory cells of the GI epithelium, enteroendocrine cells, of this chapter.
as well as neurons of the enteric nervous system are the main Demonstrating that a chemical is a neurotransmitter is
producers of chemical messengers, which are released in the perhaps more challenging, but the following criteria are
form of hormones or neurotransmitters. Enteroendocrine cells agreed to define a neurotransmitter. First, the candidate mol-
reside in the intestinal mucosa as single cells that are scattered ecule must be present within a presynaptic neuron. Second, the
among more numerous enterocytes—the absorptive cells of transmitter must be released in response to presynaptic depo-
the gut. Most enteroendocrine cells are oriented with their larization. And third, specific candidate receptors must be
apical surface open to the lumen where they are exposed to present on the postsynaptic cell.
food and other contents within the gut lumen. Upon stimula- Although hormones are commonly thought to reside
tion, enteroendocrine cells release hormones from their baso- exclusively in the endocrine system and neurotransmitters
lateral surface, and these enter the paracellular space where in the nervous system, both systems work closely together.
they are taken up into the blood. In contrast to enteroendo- Indeed, some cells exert both endocrine and neural actions.
crine cells, enteric neurons are found below the mucosal epi- For example, peripheral sensory cells such as taste cells of
thelium, and even though villi and crypts are richly innervated, the tongue and solitary chemosensory olfactory cells of the
enteric neurons are not believed to be directly exposed to food nose are known as paraneurons and can release both hormones
in the gut. in the bloodstream and neurotransmitters at synaptic con
Unlike other endocrine organs where endocrine cells are nections.4 There is growing evidence that enteroendocrine
concentrated in a single organ, the function of scattered cells have similar dual function.5,6 These observations
36
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Chapter 4 Gastrointestinal Hormones and Neurotransmitters 37
extend the continuum between the endocrine and nervous process is known as paracrine signaling and is typical of entero-
systems. endocrine cells that produce somatostatin.8 Paracrine trans-
Moreover, one transmitter can act both as a hormone and mitters are secreted locally and cannot diffuse far. They bind
a neurotransmitter, depending on its location. Upon the inges- to receptors on nearby cells to exert their biological actions.
tion of food, for example, CCK is typically released from Once released, the transmitter is rapidly taken up by the target
enteroendocrine cells into the bloodstream to act as a hormone. cell, is catabolized by extracellular enzymes, or becomes
However, CCK is also abundant in nerves of the GI tract and adherent to extracellular matrix, thus limiting the transmit-
brain, where it is released at synaptic terminals to act as a ter’s ability to act at distant sites. Because paracrine signals
neurotransmitter. This conservation of transmitters allows the act locally, their onset of action is generally rapid and can be
same messenger to have different physiologic actions at dif- terminated abruptly. By comparison, endocrine signaling
ferent locations, and is made possible by the manner in which takes much longer, and termination of signaling requires clear-
the transmitter is delivered to its target tissues. ance of hormone from the circulation. Paracrine transmitters
can be peptides (e.g., somatostatin) or monoamines (e.g.,
histamine).
Modes of Transmitter Release
Enteroendocrine transmitters can be released onto their targets Autocrine
through endocrine, paracrine, and autocrine signaling or syn- Some cells possess cell surface receptors for their own mes-
aptic neurotransmission (Fig. 4-1). sengers. In this way, when a messenger is released it can act
on the same secreting cell. This mode of transmission is known
as autocrine and has been demonstrated for several growth
Endocrine factors. Autocrine signaling has been implicated in the growth
Endocrine communication occurs when transmitters are of certain cancers, including colorectal cancer (see Chapter 1).9
secreted into the bloodstream. The most common endocrine
transmitters are peptides, lipids, and monoamines, collec-
tively known as hormones. In the GI tract the most predomi- Neurotransmission
nant type of hormone is the peptide form (e.g., peptide YY, A fourth form of signaling in the GI tract is synaptic neuro-
gastrin, secretin). Hormones bind to specific receptors on the transmission. This form of signaling is primarily used by the
surface of target cells at remote sites and regulate metabolic enteric nervous system, which is a complex network of nerve
processes.7 cells that must communicate efficiently to regulate numerous
GI functions (Fig. 4-2). When neurons of the GI tract are acti-
vated, signals in the form of neurotransmitters are released
Paracrine at nerve-to-nerve junctions known as synapses. These struc-
In contrast to endocrine mechanisms used to reach distant tures help neurons deliver neurotransmitters at specific loca-
targets through the blood, signaling cells of the GI tract can tions on the target cell and influence the function of other
also produce transmitters that act on neighboring cells. This neurons, muscle cells, epithelial and secretory cells, and other
FIGURE 4-1. Modes of transmitter release. Transmitters can be secreted from chemosensory cells and neurons in various manners:
endocrine via the blood, paracrine locally in the paracellular space, autocrine on the same releasing cell, or synaptic, allowing
neurotransmission.
38 Section I Biology of the Gastrointestinal Tract
Serosa
BOX 4-1 Hormones and Transmitters of the GI Tract
Circular Longitudinal
muscle Peptides That Function Mainly as Hormones
muscle
Gastrin
Submucosa Myenteric Glucose-dependent insulinotropic peptide (GIP)
plexus
Submucosal Glucagon and related gene products (glucagon-like peptide
plexus [GLP]-1, GLP-2, glicentin, oxyntomodulin)
Insulin
Motilin
Pancreatic polypeptide
Peptide tyrosine tyrosine (PYY)
Secretin
Peptides That May Function as Hormones,
Neuropeptides, or Paracrine Agents
Muscularis Cholecystokinin (CCK)
mucosa
Corticotropin-releasing factor (CRF)
Mucosal Endothelin
nerves Neurotensin
Mucosa Somatostatin
Peptides That Act Principally as Neuropeptides
FIGURE 4-2. Organization of the enteric nervous system. The Calcitonin gene-related peptide (CGRP)
enteric nervous system is composed of 2 major plexuses, 1 sub- Dynorphin and related gene products
mucosal and 1 located between the circular and longitudinal Enkephalin and related gene products
smooth muscle layers. These neurons receive and coordinate Galanin
neural transmission from the GI tract and central nervous Gastrin-releasing peptide (GRP)
system. Neuromedin U
Neuropeptide Y
Peptide histidine isoleucine (PHI) or peptide histidine
methionine (PHM)
specialized cells of the GI tract (e.g., enteric glia). Neurotrans- Pituitary adenylate cyclase–activating peptide (PACAP)
mitters are critical for the processes of digestion, including the Substance P and other tachykinins (neurokinin A, neurokinin B)
coordination of gut motility and secretion. Although the GI Thyrotropin-releasing hormone (TRH)
tract secretes a variety of neurotransmitters, the most common Vasoactive intestinal peptide (VIP)
are peptides like vasoactive intestinal polypeptide (VIP), or Peptides That Act as Growth Factors
small molecules like acetylcholine and norepinephrine. Other Epidermal growth factor
molecules, such as nitric oxide (NO), can simply diffuse across Fibroblast growth factor
the synaptic cleft to exert an effect on the postsynaptic cell. Insulin-like growth factors
Some nerves actually release peptides or neurotransmitters Nerve growth factor
directly into the blood. This process is called neurocrine signal- Platelet-derived growth factor
ing and may be used to cause systemic effects, depending on Transforming growth factor-β
the transmitter released. Vascular endothelial growth factor
Box 4-1 lists the major hormones and neurotransmitters of Peptides That Act as Inflammatory Mediators
the GI tract. Their actions depend on specific receptors located Interferons
on target tissues; the specificity of neurotransmitter action is Interleukins
dependent on the precise location at which the nerve synapses Lymphokines
with the target cell. Adjusting their synthesis, catabolism, or Monokines
secretion regulates the transmitter concentration within the Tumor necrosis factor-α
releasing cell. Once secreted, the concentration of a transmitter Peptides That Act on Neurons
can be quickly modulated by catabolism or, in the case of Cholecystokinin
neurotransmitters, reuptake into the secretory neuron. Many Gastrin
peptide transmitters have very short half-lives that are gener- Motilin
ally within the 2- to 5-minute range. This allows for rapid
initiation and termination of signaling. Nonpeptide Transmitters Produced in the Gut
Acetylcholine
Adenosine triphosphate (ATP)
Dopamine
TRANSDUCING SIGNALS FROM γ-Aminobutyric acid (GABA)
THE GASTROINTESTINAL LUMEN Histamine

5-Hydroxytryptamine (5-HT, serotonin)
Nitric oxide
The process of nutrient sensing involves the activation of cell Norepinephrine
surface receptors that trigger the release of transmitters. The Prostaglandins and other eicosanoids
transmitters then either enter the bloodstream or activate
sensory afferent nerves. Although the cells releasing the trans- Other Hormones or Neuropeptides
Amylin
mitters, enteroendocrine cells, are thought to interact with
Ghrelin
nerves indirectly through paracrine or endocrine signals, a
Guanylin and uroguanylin
new concept is emerging in which enteroendocrine cells and Leptin
nerves actually communicate through synaptic connections.5,6
With the use of transgenic and advanced optical tools, entero- synapses and connect to sensory neurons through synaptic-
endocrine cells have been described to have several anatomic like connections (Fig. 4-4). These connections may have broad
features observed in neurons, including dendritic-like spines applications in the biology of GI function, including the trans-
and axon-like processes. The axon-like cytoplasmic processes mission of sensory signals from nutrients and the GI micro-
vary in length from crypt to villus and from proximal to biota. Some key components involved in the transduction of
distal small intestine (Fig. 4-3). Moreover, enteroendocrine signals from the lumen of the gut to the rest of the body are
cells have the molecular components, genes, and proteins of discussed next.
FIGURE 4-3. Axon-like processes in enteroendocrine cells. Enteroendocrine cells have cytoplasmic extensions that resemble neuronal
axons. Some of these serve to act as paracrine modulators, like those in somatostatin-secreting cells; however, in other cells these
axon-like basal processes serve to connect to neurons innervating the gut.
FIGURE 4-4. Emerging model of enteroendocrine cell function, with enteroendocrine cells as paraneurons. Enteroendocrine cells connect
to afferent and efferent neurons and appear to be capable of sending and receiving neuronal signals.
Recognizing Signals Through Cell activity of an effector can be up- or down-regulated. When the
Surface Receptors interaction is completed, the GTP bound to the Gα subunit is
hydrolyzed back to GDP and dissociated from Gα. In this way,
GI epithelial cells recognize molecules in the lumen using Gα moves back to reunite with the other 2 subunits. The effec-
membrane-bound receptors. When activated, receptors trans- tor then induces an increase in the intracellular concentration
duce signals from the outside of the cell into the cytoplasm. of a second messenger. The 2 most common second messengers
Although the process is rather complex, there are key check- are cAMP and calcium, and the mechanisms involving each
points at which the signaling cascade can be regulated. Some are discussed next.
of these checkpoints occur at the moment of receptor activa-
tion, desensitization, internalization, and/or resensitization.
Because of their regulatory potential, these are attractive Signaling Through Cyclic Adenosine Monophosphate
targets for therapeutic intervention. This second messenger cAMP is a classic downstream effector
Receptors are grouped into major families depending on of β-adrenergic receptors, a family of GPCRs that have been
their structures and signaling mechanisms. The major families well characterized. These receptors are coupled to Gαs and
of cell surface receptors include G protein–coupled receptors, activate adenyl cyclase, which catalyzes the conversion of ATP
enzyme-coupled receptors, and ion channels. to cAMP. High concentrations of cAMP then modify the activ-
ity of protein kinase A (PKA), which ultimately modulates
rate-limiting enzymes involved in important physiologic func-
G Protein–Coupled Receptors tions. For example, modulation of glycogen phosphorylase
G protein–coupled receptors (GPCRs) are typified by their increases the conversion of glycogen to glucose-1 phosphate,
7-transmembrane domains. They are the most common family leading to a rise in blood glucose levels.
of protein receptors and have broad physiologic applications,
ranging from sensing light in the retina, to allowing vision to
sensing nutrients in the GI tract, to regulating food intake. Signaling Through Calcium
When stimulated by a specific ligand, GPCRs undergo confor- GPCRs associated with Gαq subunits use Ca2+ as a second
mational changes, leading to their association with a G protein, messenger (see Table 4-1). An increase in intracellular concen-
hence their name. These G proteins are bound to the intracel- trations of Ca2+ can result from the activation of voltage-gated
lular surface of the cell membrane10,11 and are composed of 3 Ca2+ channels, ligand-gated Ca2+ channels, or the release of
distinct subunits: α, β, and γ. It is the Gα subunit that confers cytosolic Ca2+ activated by membrane phospholipids. The
the name of the G protein (Table 4-1). The G proteins that latter is triggered by activation of GPCRs associated with Gαq.
stimulate an effector (e.g., adenylate cyclase) are classified as When active, Gαq moves along the cell membrane to activate
Gαs (s for “stimulatory”), whereas those that inhibit an effec- the enzyme phospholipase Cβ. Phospholipase Cβ then cleaves
tor are called Gαi (i for “inhibitory”).12-14 When the G protein the membrane phospholipid phosphatidyl inositol bisphos-
acts on the effector, this causes a rapid increase in the intracel- phate into diacylglycerol and inositol 1,4,5 trisphosphate (IP3),
lular concentrations of a second messenger (e.g., cyclic adenos- generating 2 potential signaling molecules. Diacylglycerol in
ine monophosphate [cAMP] or calcium). The second messenger the presence of Ca2+ activates protein kinase C. In addition, a
then changes the activity of one or more protein kinases to rise in Ca2+ levels from internal stores can also activate Ca2+–
catalyze the phosphorylation of an existing protein and ulti- calmodulin kinase. In this way, 2 different kinases are acti-
mately modify the physiologic activity. vated, Ca-calmodulin kinase by increasing cytosolic Ca2+ and
In general the GPCR signaling mechanism involves the protein kinase C by the action of diacylglycerol and Ca2+.
following events. In the resting state, the G protein complex These kinases then catalyze the phosphorylation of target pro-
does not interact with the receptor. When the ligand or first teins within the cell. Following receptor activation, IP3 moves
messenger binds to the receptor, the receptor changes its con- from the plasma membrane into the cytoplasm to bind IP3
formation and binds to the G protein complex. Once bound, receptors located on the endoplasmic reticulum and mito-
there is a molecular substitution in the Gα subunit—a guano- chondria. IP3 receptor binding causes release of Ca2+ from
sine diphosphate (GDP) is replaced by a guanosine triphos- intracellular organelles to further increase cytoplasmic Ca2+
phate (GTP). This replacement causes activation of the Gα concentrations. Ultimately, Ca2+ cytoplasmic concentrations
subunit. The active Gα subunit then separates from the β are restored to normal by active transport out of the cell or by
and γ subunits and moves laterally in the membrane to acti- reuptake into intracellular Ca+2 stores.
vate an effector. Working through different Gα subunits, the If the cell is over-stimulated, a process of adaptation occurs
to prevent the cell from over-responding. Attenuation of sig-
naling occurs through either ligand-induced receptor desensi-
tization or receptor internalization. The receptor is desensitized
by means of phosphorylation. Phosphorylation can also
TABLE 4-1 Classification of G Protein α Subunits and Their further label the receptor for internalization, which is accom-
Signaling Pathways plished by activation of specific receptor kinases and recruit-
ment of arrestin-like molecules that uncouple the receptor
Class Signaling Pathways from the G protein.15 Uncoupling and subsequent receptor
internalization ends signaling and eventually restores cell
Gαs Adenylate cyclase, calcium channels responsiveness.
Gαi and Gαo Adenylate cyclase, cyclic guanosine
monophosphate, phosphodiesterase, Enzyme–Coupled Receptors
c-Src, STAT 3 The most representative of the enzyme-coupled receptors
are the tyrosine kinase receptor family. These receptors
Gαq Phospholipase C-β
are primarily targets of growth factors like EGF and are
Gα12 and Gα13 Sodium-hydrogen exchange
unique in that they are both a receptor and a tyrosine
kinase. When activated, the receptors catalyze the transfer of
phosphate from ATP to the target proteins. Enzyme-coupled that fatty acids must be absorbed to stimulate CCK secretion.
receptors are composed of 3 domains: a ligand-binding Although the specific location of most nutrient receptors has
extracellular domain, a transmembrane domain, and a cyto- yet to be determined, it may be that at least some lipids have
plasmic domain. The cytoplasmic domain contains a protein to be digested and absorbed prior to activating hormone
tyrosine kinase region and substrate region for agonist- release. This hypothesis is supported by studies in which the
activated receptor phosphorylation. In this way, phosphoryla- infusion of lipid in the intestine triggers hormone secretion
tion from other kinases or autophosphorylation can occur to but only if chylomicrons, lipoprotein particles formed from
modulate the activity of the tyrosine kinase receptor.16 In absorbed lipids, are allowed to form.22
general, receptor tyrosine kinases exist in the cell membrane Some lipid-generated sensory signals appear to travel
as monomers. However, with ligand binding, these receptors through afferent fibers of the vagus nerve. Infusion of lipids
dimerize, autophosphorylate, and initiate other intracellular into the duodenum increases brown fat temperature, and this
signal transduction pathways that ultimately modulate effect is abolished if lipids are infused along with tetracaine,
physiologic function.17 Receptor tyrosine kinases are further a potent local anesthetic used to block vagal afferents activa-
discussed in Chapter 1 in relation to cellular growth and tion.23 Signals traveling through afferent nerves or the blood-
neoplasia.18 stream ultimately induce homeostatic changes (e.g., satiety,
There are several other types of enzyme-coupled receptors, body temperature, GI motility) in response to the presence of
including receptor guanylate cyclases, non-receptor tyrosine nutrients in the GI lumen.
kinases, receptor tyrosine phosphatases, and receptor serine/
threonine kinases. Although these receptors act through dif-
ferent enzymes, the signaling principles remain similar to Proteins and Amino Acids
those of tyrosine kinase receptors. Proteins can also be potent stimulants of GI hormone secre-
tion. Most proteins stimulate hormone secretion only when
digested to peptones and amino acids. Recently, enteroendo-
Ion Channel–Coupled Receptors crine cells have been found to express several classes of amino
Ion channel–coupled receptors are involved in rapid signaling acid receptors that mediate hormone secretion. The calcium-
between cells. This type of receptor is important in tissues sensing receptor (CaSR), which was originally identified for
where electrical impulses drive signaling, like nerve cells and its ability to detect and respond to extracellular Ca2+ and regu-
muscle. In nerve cells, ion channels open or close in response late calcium homeostasis in the kidney and parathyroid
to a relatively small number of neurotransmitters and allow gland,24 also recognizes L-amino acids and di- and tripep-
the flow of particular ions across the plasma membrane. The tides.25 A clear role for CaSR has been established in the regula-
kinetics of the ion flow depends on the concentration inside tion of L-amino acid–stimulated gastrin release by gastrin (G)
and outside the cell. This flow of ions regulates the excitability cells and gastric acid secretion by parietal cells.26,27 The aro-
of the target cell to ultimately trigger processes such as neu- matic amino acids phenylalanine and tryptophan are the most
rotransmission, muscle contraction, electrolyte and fluid secre- potent amino acids for stimulating CaSR and are also the most
tion, or hormone release. potent for stimulating CCK secretion. The discovery of CaSR
An example of this type of receptor is the transient receptor in CCK cells and its link to secretion support its physiologic
potential cation channel M5, better known as TRPM5. This ion importance as a nutrient sensor in the GI tract. CaSR also
channel receptor is activated by elevated intracellular Ca2+ appears to mediate the secretion of glucose-dependent insuli-
concentrations and is a key component in the transduction of notropic polypeptide (GIP), glucagon-like peptide (GLP)-1,
the taste signals bitter, sweet, and umami.19 It has been recently and peptide tyrosine tyrosine (PYY).28-30
shown to mediate the release of opioids and hormones like Another amino acid–sensing receptor closely related to
CCK from enteroendocrine cells.20 Thus, ion channel–coupled CaSR is the G protein–coupled receptor GPRC6A. GPRC6A
receptors can be attractive targets to modulate the function of responds to basic amino acids and is expressed in taste cells
sensory cells in the epithelium of the GI tract. and enteroendocrine cells of the distal small intestine where
the secretion of GLP-1 is mediated.31 Genetic deletion of
GPRC6A leads to diet-induced obesity, implying that this
receptor is important for metabolic regulation.32 Finally, the
Nutrient Chemosensing taste receptors T1R1/T1R3 also recognize acidic amino acids
and do not appear to be restricted to taste cells of the tongue,
Lipids but instead are distributed in chemosensory cells throughout
Lipids in the intestinal lumen are potent inducers of satiety the body. Together, CaSR, GPRC6A, and T1R1/T1R3 respond
and modulators of whole body metabolism. Although the to all of the 20 L-amino acids and represent a comprehensive
mechanisms are not completely understood, it has been mechanism to sense amino acid nutrient stimuli.
recently demonstrated that specific lipids are recognized by Partially digested protein in the form of peptones can
cell surface receptors that activate the release of several also stimulate hormone secretion. The G protein–coupled
hormones, including CCK, peptide YY, and glucagon-like receptor GPR93 is not only a lysophosphatidic acid receptor
peptide 1. but is also activated by peptone.33 GPR93 is expressed in
The lipids can be in the form of triglycerides or free fatty enterocytes and enteroendocrine cells, where its activation has
acids of various chain lengths. Different lipids are recognized been coupled to CCK secretion.34 Thus, GPR93 may be the
by different receptors. The Gq-coupled GPCRs 40 (i.e., FFAR1) mechanism by which peptone stimulates CCK release follow-
and 120 respond to medium- and long-chain fatty acids, ing a meal.
whereas the Gαi-coupled GPR41 (i.e., FFAR3) and GPR43 (i.e., Some intact proteins stimulate hormone secretion indi-
FFAR2) bind to short-chain fatty acids of 2 to 5 carbons.21 It rectly through a class of endogenous luminally active hormone
is possible some GPCRs respond to lipids in the lumen of releasing factors including luminal CCK releasing factor
the gut. Other non-GPCRs are also involved in lipid sensing, (LCRF)35 and diazepam binding inhibitor (DBI).36 The most
such as the immunoglobulin-like domain-containing receptor potent proteins are those that compete for trypsin binding and
(ILDR).21a ILDR is expressed in CCK cells and is activated by allow the endogenous releasing factor to escape proteolytic
the combination of fatty acids and lipoproteins, suggesting digestion within the gut lumen.
open to the gut lumen. However, this has not yet been dem-
Tastants onstrated, and recent evidence suggests that some nutrients
Sensing tastants in various foods is important to regulate plea- stimulate enteroendocrine cells when exposed to the basal
sure, reward, food intake, and other important metabolic func- lateral surface. Because gut microbiota reside in the lumen of
tions. The GI tract detects chemicals and toxins through the GI tract, it is likely that Toll-like receptors are located
specific receptors expressed by specialized chemosensory on microvilli. In the future, elucidating the location of recep-
cells. These cells are best characterized in the tongue, where tors on enteroendocrine cells may facilitate the design of
they are concentrated in taste buds. Taste receptor cells can drugs to target specific receptors and modulate the secretion
detect chemicals that give rise to the 5 different flavors: sweet, of hormones involved in appetite regulation and insulin
salty, sour, bitter, and umami—the savory taste of soy sauce. secretion.
Although this is an active area of research, only the sensing
mechanisms for sweet, bitter, and umami flavors are well
understood. These 3 flavors are mediated by the activation of
Other Factors That Stimulate Transmitter Release
2 families of GPCRs: taste-1 receptors (T1Rs) and taste-2 recep- There is evidence that GI hormones can be released by certain
tors (T2Rs). In humans, there are 30 T2R proteins and 3 T1Rs, non-nutrient factors present in the lumen of the gut (Fig.
T1R1, T1R2, and T1R3.37-39 4-5). CCK was the first hormone shown to be regulated by
Sweet and umami flavors are recognized by T1Rs. In the an intraluminal releasing factor.49,50 Luminal CCK-releasing
tongue, T1R1 and T1R2 are expressed in separate taste recep- factor (LCRF) was purified from intestinal washings and
tor cells, but always along with T1R3. In this way, the receptors shown to stimulate CCK release when instilled into the lumen
form heterodimers that allow detection of sweet ligands in the of animals. Other luminal factors causing the release of CCK
case of T1R2 + T1R3, and umami in the case of T1R1 + T1R3.40 are the diazepam-binding inhibitor (DBI) and the pancreatic
T1Rs are also expressed in enteroendocrine cells.41 Here, the monitor peptide.51,52 It has been proposed that a secretin releas-
binding of glucose to T1R2 + T1R3 receptors in enteroendo- ing factor regulates secretin secretion in an acid-sensitive
crine cells in the gut lumen leads to secretion of incretin hor- way.53 The pancreatic secretory trypsin inhibitor, better known
mones like glucagon-like peptide (GLP)-1. GLP-1 ultimately as monitor peptide, is an endogenous trypsin inhibitor pro-
modulates a wide variety of functions, including insulin secre- duced by pancreatic acinar cells.54 When secreted into the duo-
tion, nutrient absorption, and gut motility.42 Consequently, denum, monitor peptide directly stimulates CCK secretion
gut-expressed taste signaling has become an active area of from I cells. These proteins act directly on enteroendocrine
research to develop therapies for diet-related disorders like cells, most likely through cell surface receptors. The existence
type 2 diabetes.43 of these releasing factors highlights the existence of underap-
Bitter perception functions as a warning signal against the preciated bioactive molecules within the lumen of the gut.
ingestion of toxic substances through direct taste aversion,
induction of the pharyngeal gag reflex, and nausea. The wide
array of T2Rs present in the tongue and gut are set to recog- THE TRANSMITTERS
nize bitter compounds such as toxic alkaloids in plants.44 It is
believed that bitter compounds that bypass T2Rs in the tongue The same factors that stimulate transmitter release simultane-
are recognized by T2Rs in the gut, serving as a backup mecha- ously modulate the expression of specific transmitter genes.
nism for inducing a protective response such as vomiting.45 The genes for most of the known GI peptides have now been
Activation of T2Rs and their associated Gα-gustducin protein identified and are regulated within cell types by specific gene
result in a rapid increase in cytosolic Ca2+, which stimulates regulatory elements. Gut hormone gene expression is gener-
membrane depolarization and hormone release. In the gut, ally linked to peptide production and regulated according to
bitter chemicals can stimulate the release of CCK from entero- the physiologic needs of the organism. Once a biological
endocrine cells to slow gastric emptying and decrease appe- response is elicited, signals may then be sent back to the endo-
tite, reducing the likelihood of toxin absorption.42,45,46 crine cell to “turn off” hormone secretion. This negative feed-
back mechanism is common to many physiologic systems and
avoids excess production and secretion of hormone.
Sensing the Microbiome All GI peptides are synthesized via transcription of DNA
Enteroendocrine cells typically have a small, narrow opening into messenger RNA, which is subsequently translated into
to the luminal surface. Although it has been long been assumed precursor proteins known as preprohormones. The newly trans-
that nutrients stimulate enteroendocrine cells at their apical lated protein contains a signal sequence that directs it to the
portion, there are some reports that absorbed and not luminal endoplasmic reticulum to prepare the peptide precursor for
nutrients stimulate gut hormone release.22 It is possible that structural modifications.55 These precursors are transported to
the apical portion of enteroendocrine cells open to the gut the Golgi apparatus where further structure modifications
lumen may serve to sense bacterial inputs. Evidence support- occur before the peptide is packaged in secretory granules.
ing this hypothesis comes from the fact that some bacterial Secretory granules may be targeted for immediate release or
Toll-like receptors (e.g., TLRs 4, 5, and 9) are exclusively stored in close proximity to the plasma membrane, ready to
expressed in enteroendocrine cells.47 When these specific TLRs be released. Although many hormones are produced from a
are stimulated with bacterial ligands (e.g., LPS or flagellin), single gene, there can be multiple molecular forms in tissues
CCK and several chemokines are secreted. Remarkably, cyto- and blood. The different molecular forms result from differ-
kines and defensins are secreted from an enteroendocrine cell ences in pre-translational or post-translational processing. A
line (i.e., STC-1) only in response to bacterial ligands and not common pre-translational processing mechanism is the alter-
to fatty acids. Moreover, silencing MyD88, a central mediator native splicing of mRNA, which generates unique peptides
of TLR signaling, reduces CCK secretion stimulated by bacte- from the same gene.
rial ligands but not by fatty acids.48 This evidence suggests that Post-translational modifications can occur by cleavage of
there may be 2 different sensing pathways in enteroendocrine precursor molecules, where enzymatic cleavage of the signal
cells, 1 for bacteria and another for nutrients. peptide produces a prohormone. Other post-translational fea-
It has long been assumed that chemosensory receptors on tures that result in mature GI peptides include peptide cleav-
enteroendocrine cells reside on the apical surface, which is age to smaller forms (e.g., somatostatin), amidation of the
FIGURE 4-5. Regulation of CCK secretion by intraluminal releasing factors. Intestinal epithelial cells secrete factors known as CCK-
releasing factors because of their ability to stimulate CCK release from enteroendocrine cells (green). CCK is released into the blood-
stream to stimulate pancreatic secretion of monitor peptide and trypsin. Monitor peptide further stimulates the release of CCK and
constitutes a feed-forward mechanism. In turn, trypsin in the intestine digests food and inhibits the actions of monitor peptide and
CCK-releasing factor. Trypsin therefore acts as a feedback regulator.
carboxyl terminus (e.g., gastrin), and sulfation of tyrosine resi- an amidated tetrapeptide (Try-Met-Asp-Phe-NH2) carboxyl
dues (e.g., CCK). These processing steps are critical for bio- terminus, which imparts full biological activity. Modification
logical activity of the hormone. For example, sulfated CCK is by sulfation at tyrosine residues produces alternative gastrin
100-fold more potent than its unsulfated form. The vast bio- forms of equal biological potency. A nonamidated form of
chemical complexity of gastroenteropancreatic hormones is gastrin known as glycine-extended gastrin is produced by
evident in the different tissues that secrete these peptides. GI colonic mucosa. Glycine-extended gastrin has been shown in
peptides are secreted from endocrine as well as nervous tissue, animal models to stimulate proliferation of normal colonic
so the distinct tissue involved often determines the processing mucosa and enhance the development of colorectal cancer. It
steps for production of the peptide. Many hormone genes are is not known whether local production of this form of gastrin
capable of manufacturing alternatively spliced mRNAs or contributes to human colon carcinogenesis, and the receptor
proteins that undergo different post-translational processing for glycine-extended gastrin has not been identified.58
and ultimately produce hormones of different sizes. These Most gastrin is produced in endocrine cells of the gastric
modifications are important for receptor binding, signal trans- antrum.59 Much smaller amounts of gastrin are produced in
duction, and consequent cellular responses.56 The discussion other regions of the GI tract, including the proximal stomach,
that follows outlines the major characteristics of GI transmit- duodenum, jejunum, ileum, and pancreas. Gastrin has also
ters, including neuropeptides, neurotransmitters, and other been found outside the GI tract, including in the brain, adrenal
transmitters. gland, respiratory tract, and reproductive organs, although its
biological role in these sites is unknown.
The receptors for gastrin and CCK are related and consti-
Gut Neuropeptides tute the so-called gastrin-CCK receptor family. The CCK-1 and
CCK-2 (previously known as CCK-A and -B) receptor comple-
Gastrin mentary DNAs were cloned from the pancreas and brain,
As discussed in more detail in Chapter 50, gastrin is the major respectively, after which it was recognized that the CCK-2
hormone that stimulates gastric acid secretion. Gastrin was receptor is identical to the gastrin receptor of the stomach.60
found to have growth-promoting effects on the gastric mucosa The CCK-1 receptor is present in the gallbladder and, in
and possibly some cancers.57 Human gastrin is the product of most species, the pancreas. The CCK-1 receptor has a 1000-fold
a single gene located on chromosome 17. The active hormone higher affinity for CCK than for gastrin. The CCK-1 and
is generated from a precursor peptide called preprogastrin. CCK-2 gastrin receptors have over 50% sequence homology
Human preprogastrin contains 101 amino acids (AAs), includ- and respond differently to various receptor antagonists and
ing a signal peptide (21 AAs), spacer sequence (37 AAs), to gastrin.
gastrin component (34 AAs), and a 9-AA extension at the Gastrin is released from specialized endocrine cells (G
carboxyl terminus. The enzymatic processing of preprogastrin cells) into the circulation in response to a meal. The specific
produces all the known physiologically active forms of gastrin. components of a meal that stimulate gastrin release include
Preprogastrin is processed into progastrin and gastrin protein, peptides, and amino acids. Gastrin release is pro-
peptide fragments of various sizes by sequential enzymatic foundly influenced by the pH of the stomach. Fasting and
cleavage. The 2 major forms of gastrin are G34 and G17, although increased gastric acidity inhibit gastrin release, whereas a high
smaller forms exist. The common feature of all gastrins is gastric pH is a strong stimulus for its secretion.
Hypergastrinemia occurs in pathologic states associated into dogs, caused pancreatic secretion.68 Secretin is released
with decreased acid production, such as chronic atrophic gas- by acid in the duodenum and stimulates pancreatic fluid
tritis (see Chapter 52). Serum gastrin levels can also become and bicarbonate secretion, leading to neutralization of acidic
elevated in patients on prolonged acid-suppressive medica- chyme in the intestine (see Chapter 56). Secretin also inhibits
tions, such as histamine receptor antagonists and proton gastric acid secretion (see Chapter 50) and intestinal motility.
pump inhibitors. Hypergastrinemia in these conditions is Human secretin is a 27–amino acid peptide and, similar to
caused by stimulation of gastrin production by the alkaline many other GI peptides, is amidated at the carboxyl terminus.
pH environment. Another important but far less common It is the founding member of the secretin-glucagon-VIP family
cause of hypergastrinemia is a gastrin-producing tumor, also of structurally related GI hormones. Secretin is selectively
known as Zollinger-Ellison syndrome (see Chapter 33). expressed in specialized enteroendocrine cells of the small
The gastrin analog pentagastrin has been used clinically to intestine called S cells.69
stimulate histamine and gastric acid secretion in diagnostic The secretin receptor is a member of a large family of
tests of acid secretory capacity. GPCRs that is structurally similar to receptors for glucagon,
calcitonin, parathyroid hormone, pituitary adenylate cyclase–
activating peptide (PACAP), and vasoactive intestinal poly-
Cholecystokinin peptide (VIP).
CCK is a peptide transmitter produced primarily by enteroen- One of the major physiologic actions of secretin is stimula-
docrine cells of the proximal small intestine and is secreted tion of pancreatic fluid and bicarbonate secretion (see Chapter
into the blood following ingestion of a meal. Circulating CCK 56). Pancreatic bicarbonate, on reaching the duodenum, neu-
binds to specific CCK-1 receptors on the gallbladder, pancreas, tralizes gastric acid and raises the duodenal pH, thereby
smooth muscle of the stomach, and peripheral nerves to stim- “turning off” secretin release (negative feedback). It has been
ulate gallbladder contraction and pancreatic secretion, regu- suggested that acid-stimulated secretin release is regulated by
late gastric emptying and bowel motility, and induce satiety.61 an endogenous intestinal secretin-releasing factor.70 This
These effects serve to coordinate the ingestion, digestion, and peptide stimulates secretin release from S cells until the flow
absorption of dietary nutrients. Ingested fat and protein are of pancreatic proteases is sufficient to degrade the releasing
the major food components that stimulate CCK release. factor and terminate secretin release.
CCK was originally identified as a 33–amino acid peptide. Although the primary action of secretin is to produce pan-
However, since its discovery larger and smaller forms of CCK creatic fluid and bicarbonate secretion, it is also an enterogas-
have been isolated from blood, intestine, and brain. All forms trone, a substance that is released when fat is present in the
of CCK are produced from a single gene by post-translational GI lumen and that inhibits gastric acid secretion. In physio-
processing of a preprohormone. Forms of CCK ranging in size logic concentrations, secretin inhibits gastrin release, gastric
from CCK-58 to CCK-8 have similar biological activities.62 acid secretion, and gastric motility.71 The most common
CCK is the major hormonal regulator of gallbladder con- clinical application of secretin is in the diagnosis of gastrin-
traction. It also plays an important role in regulating meal- secreting tumors,72 as discussed in Chapter 33.
stimulated pancreatic secretion (see Chapter 56). In many
species, this latter effect is mediated directly through receptors
on pancreatic acinar cells, but in humans, in whom pancreatic Vasoactive Intestinal Polypeptide
CCK-1 receptors are less abundant, CCK appears to stimulate VIP is a neuromodulator that has broad significance in intes-
pancreatic secretion indirectly through enteropancreatic tinal physiology. VIP is a potent vasodilator that increases
neurons that possess CCK-1 receptors. In some species, CCK blood flow in the GI tract and causes smooth muscle relaxation
has trophic effects on the pancreas, although its potential role and epithelial cell secretion.73,74 As a chemical messenger, VIP
in human pancreatic neoplasia is speculative. CCK also has is released from nerve terminals and acts locally on cells
been shown to delay gastric emptying.63 This action may be bearing VIP receptors. VIP belongs to a family of GI peptides,
important in coordinating the delivery of food from the including secretin and glucagon, that are structurally related.
stomach to the intestine. CCK has been proposed as a major The VIP receptor is a GPCR that stimulates intracellular cAMP
mediator of satiety and food intake, an effect that is particu- generation.
larly noticeable when food is in the stomach or intestine. Like other GI peptides, VIP is synthesized as a precursor
CCK inhibits gastric acid secretion by binding to CCK-1 recep- molecule that is cleaved to an active peptide of 28 amino acids.
tors on somatostatin (D) cells in the antrum and oxyntic VIP is expressed primarily in neurons of the peripheral-enteric
mucosa. Somatostatin acts locally to inhibit gastrin release and central nervous systems (CNS) and is released along
from adjacent G cells and directly inhibits acid secretion from with other peptides, including primarily PHI and/or PHM
parietal cells.64 (see Box 4-1).75
Clinically, CCK has been used together with secretin to VIP is an important neurotransmitter throughout the
stimulate pancreatic secretion for pancreatic function testing. central and peripheral nervous systems.76 Because of its
It is also used radiographically or scintigraphically to evaluate wide distribution, VIP has effects on many organ systems;
gallbladder contractility. There are no known diseases of CCK most notably, in the GI tract, VIP stimulates fluid and
excess. Low CCK levels have been reported in individuals electrolyte secretion from intestinal epithelium and bile duct
with celiac disease who have reduced intestinal mucosal cholangiocytes.77,78
surface area and in those with bulimia nervosa.65,66 Elevated VIP, along with NO, is a primary component of nonadren-
levels of CCK have been reported in some patients with ergic, noncholinergic nerve transmission in the gut.79 GI
chronic pancreatitis (see Chapter 59), presumably because of smooth muscle exhibits a basal tone, or sustained tension,
reduced pancreatic enzyme secretion and interruption of neg- caused by rhythmic depolarizations of the smooth muscle
ative feedback regulation of CCK release.67 membrane potential. VIP serves as an inhibitory transmitter
of this rhythmic activity, causing membrane hyperpolarization
and subsequent relaxation of GI smooth muscle. Accordingly,
Secretin VIP is an important neuromodulator of sphincters of the GI
The first hormone, secretin, was discovered when it was tract, including the lower esophageal sphincter and sphincter
observed that intestinal extracts, when injected intravenously of Oddi. In certain pathologic conditions, such as achalasia
and Hirschsprung’s disease, the lack of VIP innervation is Glucagon and GLP-1 regulate glucose homeostasis.86 Glu-
believed to play a major role in defective esophageal relax- cagon is released into the blood from alpha cells in the endo-
ation and bowel dysmotility, respectively.80,81 crine pancreas in response to a meal and binds to GPCRs on
Unlike GI endocrine cells that line the mucosa of the gut, skeletal muscle and the liver to exert its glucoregulatory
VIP is produced and released from neurons, and it is likely effects. GLP-1 stimulates insulin secretion and augments the
that most measurable VIP in serum is of neuronal origin. Nor- insulin-releasing effects of glucose on the pancreatic beta cell
mally, serum VIP levels are low and do not appreciably change (see enteroinsular axis under “Diabetes and the Gastrointestinal
with a meal. However, in pancreatic cholera, also known as Tract” later in the chapter). GLP-1 analogs have been devel-
Verner-Morrison syndrome and manifested by watery diarrhea, oped for the treatment of type 2 diabetes mellitus. A long-
hypokalemia, and achlorhydria,82 VIP levels can be extraordi- acting human GLP-1 analog improves beta cell function and
narily high.77 VIP-secreting tumors usually produce a volumi- can lower body weight in patients with type 2 diabetes.87,88
nous diarrhea (see Chapter 33).83 GLP-2 is an intestinal growth factor that increases villus
height, stimulates intestinal crypt proliferation and prevents
enterocyte apoptosis. GLP-2 agonists have therapeutic impli-
Glucagon cations in the maintenance of the GI mucosal mass and the
Glucagon is synthesized and released from pancreatic alpha reversal of villus atrophy and are being developed for the
cells and from intestinal L cells of the ileum and colon. Pan- treatment of short bowel syndrome.
creatic glucagon is a 29–amino acid peptide that regulates
glucose homeostasis via gluconeogenesis, glycogenolysis,
and lipolysis and is counter-regulatory to insulin. The gene Glucose-Dependent Insulinotropic Polypeptide
for glucagon encodes not only preproglucagon but also GIP was discovered based on its ability to inhibit gastric acid
glucagon-like peptides (GLPs). This precursor peptide con- secretion (enterogastrone effect) and was originally termed
sists of a signal peptide, a glucagon-related polypeptide, gastric inhibitory polypeptide. It was subsequently shown that
glucagon, and GLP-1 and GLP-2. Tissue-specific peptide pro- the effects on gastric acid secretion occur only at very high
cessing occurs through prohormone convertases that produce concentrations that are above the physiologic range. However,
glucagon in the pancreas and GLP-1 and GLP-2 in the intestine GIP has potent effects on insulin release that (like GLP-1)
(Fig. 4-6).84,85 potentiates glucose-stimulated insulin secretion.89 Based on
FIGURE 4-6. Post-translational processing of glucagon. The glucagon gene is transcribed and translated into proglucagon, a precursor
peptide. Proglucagon undergoes enzymatic cleavage (yellow box). The product of the cleavage depends on the type of enzyme. PC2
expressed in the pancreas cleaves proglucagon into active glucagon, whereas PC1/3 expressed in the intestine cleaves proglucagon
into a peptide fragment that gives rise to glucagon-like peptide (GLP)-1 and GLP-2. In the intestine, GLP-1 is further processed into
smaller fragments with different bioactive functions. Some of the enzymes involved in the process are dipeptidyl peptidase-4 (DPP4)
and neutral endopeptidase (NEP). GRPP, glicentin-related pancreatic polypeptide.
this action, GIP was redefined as glucose-dependent insulinotro- to specific receptors in lamina I of the spinal cord.107 Three
pic polypeptide. receptors for this family of peptides have been identified:
GIP is a 42–amino acid peptide produced by K cells in the NK-1, NK-2, and NK-3.108 Substance P is the primary ligand
mucosa of the small intestine. GIP is released into the blood for the NK-1 receptor, neurokinin A for the NK-2 receptor, and
in response to ingestion of glucose or fat. In the presence of neurokinin B for the NK-3 receptor. However, all these pep-
elevated blood glucose levels, GIP binds to its receptor on tides can bind and signal through all 3 receptor subtypes.
pancreatic beta cells, activating adenylate cyclase and other Substance P has been implicated as a primary mediator of
pathways that increase intracellular calcium concentrations, neurogenic inflammation. In the intestine, Clostridium difficile–
leading to insulin secretion. Importantly, however, the effects initiated experimental colitis results from toxin-induced
on insulin secretion occur only if hyperglycemia exists; GIP release of substance P and consequent activation of the NK-1
does not stimulate insulin release under normoglycemic receptor.109 These inflammatory sequelae can be blocked by
conditions. substance P receptor antagonists. Substance P receptors are
GIP receptors are also expressed on adipocytes through more abundant in the intestine of patients with ulcerative
which GIP augments triglyceride storage, which may contrib- colitis and Crohn’s disease.110 NK-1 receptor antagonists such
ute to fat accumulation. Based on the insulinotropic properties as aprepitant are potent antiemetic drugs (see Chapter 15).
of GIP, coupled with its effects on adipocytes, it has been pro-
posed that GIP may play a role in obesity and development of
insulin resistance associated with type 2 diabetes mellitus.90 Somatostatin
Consistent with this proposal was the experimental finding Somatostatin is a 14–amino acid cyclic peptide that was ini-
that mice lacking the GIP receptor do not gain weight when tially identified as an inhibitor of growth hormone secretion.
placed on a high-fat diet.91 It remains to be seen whether GIP Since its discovery, it has been found in almost every organ in
antagonists can be used to treat obesity. In rare circumstances, the body and throughout the GI tract. In the gut, somatostatin
receptors for GIP may be aberrantly expressed in the adrenal is produced by D cells in the gastric and intestinal mucosa and
cortex, resulting in food-dependent Cushing’s syndrome.92,93 islets of the pancreas, as well as enteric neurons.111 Somatosta-
tin has a number of pharmacologic effects that are mostly
inhibitory.
Pancreatic Polypeptide Family In the stomach, somatostatin plays an important role in
Originally isolated during the preparation of insulin, pancre- regulating gastric acid secretion.112 In the antrum, D cells are
atic polypeptide (PP) is the founding member of the PP open to the lumen, where they are directly exposed to acid. A
family.94 The PP family of peptides includes neuropeptide Y low gastric pH stimulates D cells that lie in close proximity
(NPY) and peptide tyrosine tyrosine (PYY), which were dis- to gastrin-producing cells to secrete somatostatin and inhibit
covered because of the presence of a C-terminal tyrosine gastrin release by a paracrine effect (see Chapter 50). Reduced
amide.95,96 PP is stored and secreted from specialized pancre- gastrin secretion decreases the stimulus for acid production
atic endocrine cells (PP cells),97 whereas NPY is a principal and the pH of the stomach contents rises. Thus, some of the
neurotransmitter found in the central and peripheral nervous inhibitory effects of gastric acid on gastrin release (see earlier,
systems.98 PYY has been localized to enteroendocrine cells “Gastrin”) are mediated by somatostatin.
throughout the GI tract but is found in greatest concentrations Somatostatin release is also influenced by mechanical stim-
in the ileum and colon, where it is produced in L cells along ulation, dietary components of a meal, including protein, fat,
with glucagon-like peptides.99 and glucose, and other hormones and neurotransmitters.113
The PP-PYY-NPY family of peptides functions as endo- Muscarinic stimulation appears to be the most important
crine, paracrine, and neurocrine transmitters in the regulation neural stimulus to somatostatin secretion.
of a number of actions that result from binding to 1 of 5 recep- At least 5 somatostatin receptors have been identified that
tor subtypes.100 PP inhibits pancreatic exocrine secretion, gall- account for divergent pharmacologic properties.114 Receptor
bladder contraction, and gut motility.101 PYY inhibits vagally subtypes 2 and 3 couple to inhibitory G proteins, but receptor
stimulated gastric acid secretion and other motor and secre- subtype 1 does not. Only somatostatin receptor subtype 3
tory functions.102 An abbreviated form of PYY lacking the first inhibits adenylate cyclase. The inhibitory effects of somatosta-
2 amino acids of the normally produced 36 amino acid peptide, tin are mediated by a decrease in cAMP, Ca2+ channel inhibi-
PYY3-36, has been shown to reduce food intake when adminis- tion, or K+ channel opening.
tered to humans, indicating that intestinally released peptide In the gut, somatostatin has broad inhibitory actions. In
may play a role in regulating meal size.103 NPY is one of the addition to effects on gastric acid, somatostatin reduces pep-
most abundant peptides in the CNS and, in contrast to PYY3-36, sinogen secretion. Somatostatin profoundly inhibits pancre-
is a potent stimulant of food intake.104 Peripherally, NPY atic enzyme, fluid, and bicarbonate secretion and reduces bile
affects vascular and GI smooth muscle function.105 flow.115 The effects of somatostatin on gut motility are largely
inhibitory, with the exception that it stimulates the migrating
motor complex, possibly through effects on motilin. Soma-
Substance P and the Tachykinins tostatin also reduces intestinal transport of nutrients and fluid,
Substance P belongs to the tachykinin family of peptides, reduces splanchnic blood flow, and has inhibitory effects on
which includes neurokinin A and neurokinin B. The tachyki- tissue growth and proliferation.116,117
nins are found throughout the peripheral and central nervous Because of its varied physiologic effects, somatostatin has
systems and are important mediators of neuropathic inflam- several clinically important pharmacologic uses. Many endo-
mation.106 Tachykinins, as a group, are encoded by 2 genes crine cells possess somatostatin receptors and are sensitive
that produce preprotachykinin A and pre-protachykinin B. to inhibitory regulation. Therefore, somatostatin and more
Common to both is a well-conserved C-terminal pentapeptide. recently developed somatostatin analogs are used to treat con-
Transcriptional and translational processing produce sub- ditions of hormone excess produced by endocrine tumors
stance P, neurokinin A, and/or neurokinin B, which are regu- (e.g., acromegaly, carcinoid tumors, islet cell tumors [includ-
lated in large part by alternative splicing. These peptides ing gastrinomas]).118 Its ability to reduce splanchnic blood flow
function primarily as neuropeptides. Substance P is a neu- and portal venous pressure has led to somatostatin analogs
rotransmitter of primary sensory afferent neurons and binds being used to treat esophageal variceal bleeding (see Chapter
92).119 The inhibitory effects on secretion have been exploited this condition is extremely rare.132,133 Mutation of the leptin
by using somatostatin analogs to treat some forms of diarrhea receptor has been described as a cause of obesity in at least
and reduce fluid output from pancreatic fistulas. Many endo- one family.134
crine tumors express abundant somatostatin receptors, making
it possible to use radiolabeled somatostatin analogs (e.g.,
octreotide) to image even small tumors throughout the body. Ghrelin
Ghrelin is a 28–amino acid peptide produced by the stomach
and is the natural ligand for the growth hormone secretagogue
Motilin (GHS) receptor.135 When administered centrally or peripher-
Motilin is a 22–amino acid peptide produced by endocrine ally, ghrelin stimulates growth hormone secretion, increases
cells of the duodenal epithelium.120 It is not released by the food intake, and produces weight gain.136,137 Circulating ghrelin
stimulation of food but instead is secreted into the blood levels increase during periods of fasting or under conditions
under fasting conditions in a periodic and recurrent pattern associated with negative energy balance, such as starvation or
that is synchronized with the migrating motor complex anorexia. In contrast, ghrelin levels are low after eating and in
(MMC). Elevations in blood motilin levels regulate the phase obesity. Ghrelin appears to play a central role in the neurohor-
III contractions that initiate in the antroduodenal region and monal regulation of food intake and energy homeostasis.
progress toward the distal gut. The gastric fundus is the most abundant source of ghrelin,
Motilin binds to specific receptors on smooth muscle cells although lower amounts of ghrelin are found in the intestine,
of the esophagus, stomach, and small and large intestines pancreas, pituitary, kidney, and placenta. Ghrelin is produced
through which it exerts propulsive activity.121 Agonists to the by distinctive endocrine cells known as P/D1 cells138,139 that are
motilin receptor (e.g., erythromycin) have pronounced effects of 2 types, open and closed. The open type is exposed to the
on GI motility, which occasionally produces undesired side lumen of the stomach, where it comes into contact with gastric
effects of abdominal cramping and diarrhea.122 However, contents, whereas the closed type lies in close proximity to the
motilin agonists may be useful to treat conditions of impaired capillary network of the lamina propria.140 Both cell types
gastric and intestinal motility and are being investigated for secrete hormone into the bloodstream. Based on its structure,
the treatment of constipation-predominant irritable bowel ghrelin is a member of the motilin family of peptides and, like
syndrome.123 motilin, ghrelin stimulates gastric contraction and enhances
stomach emptying.
The observations that circulating ghrelin levels increase
Leptin sharply before a meal and fall abruptly after a meal suggest
Leptin is a 167–amino acid protein that is secreted primarily that it serves as a signal for initiation of feeding. The inhibitory
from adipocytes. Blood leptin levels reflect total body fat effects of food on plasma ghrelin levels can be reproduced by
stores.124 Small amounts of leptin are produced by the chief ingestion of glucose and appear to be unrelated to the physical
cells of the stomach and by the placenta and are present in effects of a meal on gastric distention. Circulating ghrelin
breast milk. Its primary action appears to be to reduce food levels are low in states of positive energy balance such as
intake. Leptin is a member of the cytokine family of signaling obesity and are inversely correlated with body mass index.141,142
molecules. Five different forms of leptin receptors have been Conversely, ghrelin levels are high in fasting, cachexia, and
reported.125 A short form of the receptor appears to transport anorexia. Importantly, weight loss increases circulating ghrelin
leptin from the blood across the blood-brain barrier, where it levels.143
has access to the hypothalamus. A long form of the leptin Ghrelin released from the stomach acts on the vagus nerve
receptor is located in hypothalamic nuclei, where leptin binds to exert its effects on feeding. However, it is also active when
and activates the Janis kinase signal transduction and transla- delivered to the CNS and, in this location, ghrelin activates
tion system (JAK STAT).126 NPY- and agouti-related protein-producing neurons in the
Peripheral administration of leptin reduces food intake. arcuate nucleus of the hypothalamus, which is involved in the
However, this effect is reduced as animals become obese. regulation of feeding.137,144
Interestingly, when injected into the CNS, obese animals Gastric bypass patients do not demonstrate the premeal
respond normally to leptin and reduce food intake, suggesting increase in plasma ghrelin that is seen in normal individuals.145
that leptin “resistance” in obesity occurs at the level of the This lack of ghrelin release may be one of the mechanisms
leptin receptor that transports leptin across the blood-brain contributing to the overall effectiveness of gastric bypass
barrier.127 Leptin’s ability to reduce food intake occurs within surgery for inducing weight loss.
the brain by decreasing NPY (a potent stimulant of food Prader-Willi syndrome is a congenital obesity syndrome
intake) and by increasing α-melanocyte-stimulating hormone characterized by severe hyperphagia, growth hormone defi-
(α-MSH), an inhibitor of food intake.128 Peripherally, leptin ciency, and hypogonadism. Although common obesity is ordi-
acts synergistically with CCK to reduce meal size.129 In obese narily associated with low ghrelin levels, patients with
rats lacking the leptin receptor, the synergistic effects of leptin Prader-Willi syndrome have high circulating ghrelin levels
plus CCK to reduce meal size are lost but could be restored that do not decline after a meal.146,147 The levels of ghrelin in
with genetic reconstitution of the leptin receptor in the brain.130 this syndrome are similar to those that can stimulate appetite
One might expect loss of leptin-CCK synergy on meal size in and increase food intake in individuals receiving infusions of
those rare cases of human obesity caused by leptin receptor exogenous ghrelin, suggesting that abnormal ghrelin secretion
defects or even with leptin resistance. may be responsible for the hyperphagia in Prader-Willi
Blood levels of leptin increase as obesity develops, and syndrome.148
leptin appears to reflect total fat content.131 At the cellular
level, large adipocytes produce more leptin than small adipo-
cytes. Because of its effects on food intake, it was initially
Neurotransmitters
thought that exogenous leptin could be used therapeutically
to treat obesity. However, only a very modest effect on weight Acetylcholine
loss has been demonstrated in clinical trials. Leptin deficiency Acetylcholine is synthesized in cholinergic neurons and is the
has been reported as a cause of obesity in a few families, but principal regulator of GI motility and pancreatic secretion.
Acetylcholine is stored in nerve terminals and released by subtype has a specific pharmacologic profile when exposed to
nerve depolarization. Released acetylcholine binds to postsyn- agonists and antagonists. After release from the nerve termi-
aptic muscarinic and/or nicotinic receptors. Nicotinic acetyl- nal, dopamine is cleared from the synaptic cleft by a specific
choline receptors belong to a family of ligand-gated ion dopamine transporter.
channels and are homopentamers or heteropentamers com-
posed of α, β, γ, δ, and ε subunits.149 The α subunit is believed
to be the mediator of postsynaptic membrane depolarization Serotonin
following acetylcholine receptor binding. Muscarinic recep- Serotonin (5-hydroxytryptamine [5-HT]) has long been known
tors belong to the heptahelical GPCR family. There are 5 to play a role in GI neurotransmission.152 The GI tract contains
known muscarinic cholinergic receptors (M1 to M5). Musca- more than 95% of the total body serotonin, and serotonin is
rinic receptors can be further classified based on receptor important in various processes, including epithelial secretion,
signal transduction, with M1, M3, and M5 stimulating adenyl- bowel motility, nausea, and emesis.153 Serotonin is synthesized
ate cyclase and M2 and M4 inhibiting this enzyme. Acetylcho- from tryptophan, an essential amino acid, and is converted to
line is degraded by the enzyme acetylcholinesterase, and the its active form in nerve terminals. Secreted serotonin is inac-
products may be recycled through high-affinity transporters tivated in the synaptic cleft by reuptake via a serotonin-specific
on the nerve terminal. transporter. Most plasma serotonin is derived from the gut,
where it is found in mucosal enterochromaffin cells and the
enteric nervous system. Serotonin mediates its effects by
Catecholamines binding to a specific receptor. There are 7 different serotonin
The primary catecholamine neurotransmitters of the enteric receptor subtypes found on enteric neurons, enterochromaffin
nervous system include norepinephrine and dopamine. Nor- cells, and GI smooth muscle (5-HT1 to 5-HT7).
epinephrine is synthesized from tyrosine and released from The actions of serotonin are complex (Fig. 4-7).154 It can
postganglionic sympathetic nerve terminals that innervate cause smooth muscle contraction through stimulation of cho-
enteric ganglia and blood vessels. Tyrosine is converted to linergic nerves or relaxation by stimulating inhibitory NO-
dopa by tyrosine hydroxylase. Dopa is initially converted into containing neurons.153 Serotonin released from mucosal cells
dopamine by dopa decarboxylase and packaged into secretory stimulates sensory neurons, initiating a peristaltic reflex and
granules. Norepinephrine is formed from dopamine by the secretion (via 5-HT4 receptors) and modulates sensation
action of dopamine β-hydroxylase in the secretory granule. through activation of 5-HT3 receptors.152 The myenteric plexus
After an appropriate stimulus, norepinephrine-containing contains serotoninergic interneurons that project to the submu-
secretory granules are released from nerve terminals and bind cosal plexus and ganglia extrinsic to the bowel wall. Extrinsic
to adrenergic receptors. neurons activated by serotonin participate in bowel sensation
Adrenergic receptors are G protein–coupled, have 7 typical and may be responsible for abdominal pain, nausea, and
membrane-spanning domains, and are of 2 basic types, α and symptoms associated with irritable bowel syndrome. Intrinsic
β. α-Adrenergic receptors are further classified into α1A, α1B, neurons activated by serotonin are primary components of the
α2A, α2B, α2C, and α2D. Similarly, β receptors include β1, β2, and peristaltic and secretory reflexes responsible for normal GI
β3. Adrenergic receptors are known to signal through various function. Serotonin may also activate vagal afferent pathways
G proteins, resulting in stimulation or inhibition of adenylate and, in the CNS, modulates appetite, mood, and sexual func-
cyclase and other effector systems. Norepinephrine signaling tion. Because of these diverse effects, it is not surprising that
is terminated by intracellular monoamine oxidase or by rapid selective serotonin reuptake inhibitor drugs (SSRIs), com-
reuptake by an amine transporter. The actions of adrenergic monly used to treat depression and anxiety, have prominent
receptor stimulation regulate smooth muscle contraction, GI side effects when compared with placebo treatment.
intestinal blood flow, and GI secretion. Serotonin and its receptor have been implicated in the
pathogenesis of motility disorders of the GI tract.155 Character-
ization of specific serotonin receptor subtypes has led to the
Dopamine development of selective agonists and antagonists for the
Dopamine is an important mediator of GI secretion, absorp- treatment of irritable bowel syndrome and chronic constipa-
tion, and motility and is the predominant catecholamine neu- tion and diarrhea. For example, 5-HT3 receptor antagonists,
rotransmitter of the central and peripheral nervous systems. which reduce intestinal secretion, are used to treat diarrhea-
In the CNS, dopamine regulates food intake, emotions, and predominant irritable bowel syndrome. 5-HT4 receptor
endocrine responses. Peripherally, it controls hormone secre- agonists elicit prokinetic effects and are used to treat
tion, vascular tone, and GI motility. Characterization of dopa- constipation-predominant irritable bowel syndrome and other
mine in the GI tract has been challenging for several reasons. motility disorders.156,157
First, dopamine can produce inhibitory and excitatory effects Serotonin can also be enzymatically converted to melato-
on GI motility.150 Generally the excitatory response, which is nin by serotonin N-acetyltransferase.158 Other than the pineal
mediated by presynaptic receptors, occurs at a lower agonist gland, the GI tract is the major source of the body’s melato-
concentration than the inhibitory effect, which is mediated by nin. Melatonin is produced in enterochromaffin cells and
postsynaptic receptors. Second, localization of dopamine released into the blood after ingestion of a meal. A number of
receptors has been hampered by identification of dopamine actions on the GI tract have been described for melatonin,
receptors in locations that appear to be species specific.151 including reducing gastric acid and pepsin secretion, induc-
Third, studies of dopamine in GI tract motility have often used ing smooth muscle relaxation, and preventing epithelial
pharmacologic amounts of this agonist. Therefore, the inter- injury through an antioxidant effect.159 It has been proposed
pretation of results has been confounded by the ability of that melatonin released after a meal may contribute to post-
dopamine to activate adrenergic receptors at high doses. prandial somnolence.160
Classically, dopamine was thought to act via 2 distinct
receptor subtypes, type 1 and type 2. Molecular cloning has
now demonstrated 5 dopamine receptor subtypes, each with Histamine
a unique molecular structure and gene locus.151 Dopamine In the GI tract, histamine is best known for its central role in
receptors are integral membrane GPCRs, and each receptor regulating gastric acid secretion (see Chapter 50) and intestinal
FIGURE 4-7. Serotonin in the enteric nervous system. About 90% of the body’s serotonin is produced by enterochromaffin cells (green)
of the intestinal epithelium. Like enteroendocrine cells, enterochromaffin cells are sensory cells that release serotonin, also known as
5-hydroxytryptamine (5-HT), in response to GI luminal contents. Released 5-HT stimulates afferent fibers of the vagus nerve, which
carry sensory information to the brain. Cell bodies of these vagal neurons are clustered in the nodose ganglia. 5-HT can also stimulate
nerve fibers from neurons in the submucosal plexus or myenteric plexus. Information integrated at these plexuses ultimately regulates
excitation or inhibition of both the circular and/or longitudinal smooth muscle. Synchronous contraction of these 2 layers of smooth
muscle ultimately allows churning and propelling the chyme (partly digested food).
motility. Histamine is produced by enterochromaffin-like cells active. Small changes in NOS activity can occur through eleva-
of the stomach and intestine as well as enteric nerves. Hista- tions in intracellular calcium. The inducible form of NOS (type
mine is synthesized from l-histidine by histidine decarboxyl- II) is apparent only when cells become activated by specific
ase and activates 3 GPCR subtypes. H1 receptors are found on inflammatory cytokines. This form of NOS is capable of pro-
smooth muscle and vascular endothelial cells and are linked ducing large amounts of NO and is calcium independent. NOS
to phospholipase C (PLC) activation. As such, the H1 receptor is often co-localized with VIP and PACAP in neurons of the
mediates many of the allergic responses induced by histamine. enteric nervous system.163
H2 receptors are present on gastric parietal cells, smooth NO, being an unstable gas, has a relatively short half-life.
muscle, and cardiac myocytes. H2 receptor binding stimulates Unlike most neurotransmitters and hormones, NO does not
Gs (G proteins that stimulate adenylate cyclase) and activates act via a membrane-bound receptor. Instead, NO readily dif-
adenylate cyclase. H3 receptors are present in the CNS and GI fuses into adjacent cells to activate guanylate cyclase directly
tract enterochromaffin cells. These receptors signal through Gi (Fig. 4-8). NO activity is terminated by its oxidation to nitrate
and inhibit adenylate cyclase.161 Histamine can also interact and nitrite. Many enteric nerves use NO to signal neighboring
with the N-methyl-d-aspartate (NMDA) receptor and enhance cells and induce epithelial secretion, vasodilation, or muscle
activity of NMDA-bearing neurons independently of the 3 relaxation. NO is also produced by macrophages and neutro-
known histamine receptor subtypes. phils to help kill invading organisms.164
Unlike other neurotransmitters, there is no known trans-
porter responsible for termination of histamine’s action.
However, histamine is metabolized to telemethylhistamine by
Cannabinoids and Other Chemical Transmitters
histamine N-methyltransferase and is then degraded to tele-
methylimidazoleacetic acid by monoamine oxidase B and an Cannabinoids
aldehyde dehydrogenase. There are 3 categories of cannabinoids: synthetic, phyto
cannabinoids found in plants, and endocannabinoids.
Endocannabinoids in particular have similar functions to neu-
Nitric Oxide rotransmitters, in that they participate in synaptic transmis-
NO is a unique chemical messenger produced from l-arginine sion.165 In contrast to typical neurotransmitters, however, the
by the enzyme nitric oxide synthase (NOS).162 Three types of flow of endocannabinoid signaling is retrograde to conven-
NOS are known. Types I and III are also known as endothelial tional neurotransmitters.166 Because of their liphophilic nature,
NOS and neuronal NOS, respectively, and are constitutively endocannibinoids are membrane-bound molecules thought
FIGURE 4-8. Relaxing smooth muscle tone through nitric oxide (NO). NO, synthesized from arginine by nitric oxide synthase, diffuses
across the plasma membrane into smooth muscle cells. NO binds to and activates guanylate cyclase, which converts guanosine
triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); cGMP causes smooth muscle relaxation. (Modified from Alberts B,
Bray D, Lewis J, et al, editors. Molecular biology of the cell. 4th ed. New York: Garland Science; 2002. p 831.)
to be enriched in postsynaptic neurons. Thus, when released, proliferation, immunity, and inflammation. Cytokines are
endoccanabinoids move from postsynapses to act on presyn- induced by specific stimuli, such as toxins produced by patho-
aptic cannabinoid receptors and depress presynaptic func- gens, and often elicit a complex response involving other
tion.167 In this manner, endocannabinoid signaling helps cellular mediators to eradicate the foreign substance. Cyto-
postsynaptic neurons regulate the secretion of transmitters kines may be categorized as interleukins (ILs), TNFs, lympho-
from the sensory cell. toxins, interferons (IFNs), colony-stimulating factors (CSFs),
There are several types of endocannabinoid ligands, and others.170 Interleukins can be further subtyped into at least
including arachidonoylethanolamine (anandamide), 2- 35 separate substances, IL-1 to IL-35. There are 2 TNFs, TNF-α
arachidonoyl (2-AG), 2-arachidonyl glyceryl ether (Noladin and TNF-β (also known as lymphotoxin-α). IFNs are produced
ether), N-arachidonoyl-dopamine (NADA), virodhamine during viral or bacterial infection and come in 2 varieties,
(OAE), and lysophosphatidylinositol. Endocanabinoids, as IFN-α (also known as leukocyte-derived interferon or interferon-β)
well as other cannabinoids, modulate metabolism and behav- and IFN-γ. IFN-α is produced by T lymphocytes and is used
ior by acting on the GPCR cannabinoid receptors CB1 and clinically for the treatment of viral hepatitis (see Chapters 79
CB2. Both receptors are distributed throughout the body, and 80). The major CSFs are granulocyte mononuclear phago-
although CB1 is primarily found in neurons and epithelial cyte CSF, mononuclear phagocyte CSF, and granulocyte CSF.
chemosensory cells, and CB2 is mainly present in cells of the These agents are used for chemotherapy-induced neutropenia
immune system. and marrow support after bone marrow transplantation. Che-
In the GI tract, CB1 receptors are also involved in counter- mokines initiate and propagate inflammation and are of 2
acting proinflammatory responses and preventing the groups, CXC (α chemokines) and CC (β chemokines). Other
development of colitis.168 In addition to activating classical cytokines, such as transforming growth factor (TGF)-β and
cannabinoid receptors, endocannabinoids can also stimulate platelet-derived growth factor (PDGF), have proliferative
GPCRs such as GPR119. Importantly, GPR119 is a receptor effects.
found in enteroendocrine cells of the small intestine, and its
activation by endocannabinoids triggers the release of satiety-
inducing hormones like CCK and peptide YY.168 These find-
ings have made the field of GI endoccanabinoid research an
THE IMPORTANCE OF HORMONES
active area for the development of therapeutic treatments. AND NEUROTRANSMITTERS
Adenosine Growth and Abnormal Growth of
Adenosine is an endogenous nucleoside that acts through any
the Gastrointestinal Mucosa
of 4 GPCR subtypes.169 Adenosine causes relaxation of intesti- Growth of GI tissues is a balance between cellular prolifera-
nal smooth muscle and stimulates intestinal secretion. Ade- tion and senescence. Many factors participate in maintenance
nosine can also cause peripheral vasodilation and activation of the GI mucosa. Nutrients and other luminal factors stimu-
of nociceptors that participate in neural pain pathways. late growth of the intestinal mucosa and are necessary to
maintain normal digestive and absorptive functions. Hor-
mones and transmitters serve as secondary messengers that
Cytokines are normally secreted in response to food ingestion and
Cytokines are a group of polypeptides produced by mediate many of the nutrient effects on the GI tract. They play
various immunomodulatory cells and are involved in cell a key role in cellular proliferation. Alterations in intestinal
proliferation are manifested by atrophy, hyperplasia, dyspla- be important for growth of certain types of cancers, particu-
sia, or malignancy (see Chapter 1). larly lung and colon cancer.
These responses are mediated by specific growth factors.
There are several growth factors that have important effects
on the GI tract, including peptides of the EGF, TGF-β, IGF, Epidermal Growth Factor
FGF, and PDGF families, hepatocyte growth factors, trefoil EGF was the first growth factor to be discovered. It is the
factors, and many cytokines (including ILs).171 Below are out- prototype for a family of growth factors that are structurally
lined important properties of some of these receptors. related and have similarly related receptors. Other members
of the family include TGF-α, amphiregulin, and heparin-
binding EGF. EGF is identical to urogastrone (originally iso-
Growth Factor Receptors lated from urine), which was shown to inhibit gastric acid
Growth factors regulate cellular proliferation by interacting secretion and promote healing of gastric ulcers. EGF is secreted
with specific cell surface receptors. These receptors are mem- from submaxillary glands and Brunner’s glands of the duode-
brane proteins that possess specific binding sites for the num. It is likely that EGF interacts with luminal cells of the GI
growth factor ligand. An unusual form of signaling occurs tract to regulate proliferation. EGF has important trophic
when the ligand interacts with its receptor within the same effects on gastric mucosa, and the wide distribution of EGF
cell. For example, PDGF receptors present on the intracellular receptors suggests that EGF has mitogenic actions on various
surface of fibroblast cell lines are activated by intracellular cells throughout the gut. The EGF receptor has been reported
ligand. This process is known as intracrine signaling. Most to be responsible for gastric hyperplasia in patients with
peptide growth factors, however, interact with receptors on Ménétrier’s disease.173 Moreover, 2 patients were effectively
different cells to regulate proliferation. treated with a monoclonal antibody that blocks ligand binding
Growth factor receptors can be single polypeptide chains to the EGF receptor.174 EGF receptors are important targets for
containing 1 membrane-spanning region, such as the receptor the treatment of human cancer, including metastatic colorectal
for EGF, or they may be composed 2 subunit heterodimers, cancer.175
with 1 subunit containing a transmembrane domain and the
other residing intracellularly but covalently bound to the
transmembrane subunit. Heterodimers may also dimerize to Transforming Growth Factor-α
form a receptor composed of 4 subunits (e.g., IGF receptor). TGF-α is produced by most epithelial cells of the GI tract
Binding of the ligand to its receptor usually causes aggrega- and acts through the EGF receptor. Therefore, it shares
tion of 2 or more receptors and activation of intrinsic tyrosine trophic properties with EGF. It is believed to play a key role
kinase activity. Growth factor receptors also have the ability in gastric reconstitution after mucosal injury. Moreover, this
to autophosphorylate when bound to ligand. In addition, peptide appears to be important in GI neoplasia, because
receptor tyrosine kinase activity may phosphorylate other most gastric and colon cancers produce TGF-α (see Chapters
intracellular proteins important in signal transduction. Auto- 54 and 127).
phosphorylation attenuates the receptor’s kinase activity and
often leads to down-regulation and internalization of the
receptor. Mutation of the receptor at its autophosphorylation Transforming Growth Factor-β
site may lead to constitutive receptor activity and cellular A family of TGF-β peptides exerts various biological actions,
transformation. Growth factor receptors may couple to various including stimulation of proliferation, differentiation, embry-
intracellular signaling pathways, including adenylate cyclase, onic development, and formation of extracellular matrix.176 In
phospholipase C, calcium-calmodulin protein kinases, MAP contrast with the TGF-α receptor, there are 3 distinct TGF-β
kinase, and nuclear transcription factors. Thus, growth factors receptors.177 TGF-β modulates cell growth and proliferation
play important and varied roles in most cells of the GI tract. in nearly all cell types and can enhance its own production
It is not surprising, therefore, that mutations in growth factor from cells. It is likely that TGF-β plays a critical role in inflam-
receptors or downstream signaling proteins can lead to unreg- mation and tissue repair. TGF-β augments collagen produc-
ulated cell growth and neoplasia (see Chapter 1). tion by recruitment of fibroblasts through its chemoattractant
An important action of growth factors is their ability to properties. This action can have beneficial or deleterious
modulate the expression of transacting transcription factors effects, depending on its site of deposition and abundance. For
that can regulate expression of many other genes.172 Early example, TGF-β may play a key role in the development of
response genes such as jun and fos are activated rapidly after adhesions following surgery.178
ligand binding and control the expression of many other genes
involved in cellular proliferation. Other important transcrip-
tional factors include c-myc and nuclear factor (NF)-κB. The Insulin-like Growth Factors
latter is found in the cytoplasm in an inactive form and, fol- Alternative splicing of the insulin gene produces 2 structurally
lowing ligand binding, translocates to the nucleus, where it related peptides, insulin-like growth factor (IGF) I and IGF
activates other transcription factors. NF-κB is a key target for II.179 IGFs signal through at least 3 different IGF receptors. The
strategies to regulate cellular proliferation and inflammation. IGF I receptor is a tyrosine kinase, and the IGF II receptor is
In its phosphorylated form Rb-1, originally identified in reti- identical to the mannose 6-phosphate receptor. Although the
noblastoma, is an inhibitor of cellular proliferation that com- exact function of IGFs in the GI tract is not clearly understood,
plexes with the transcription factor p53. Dephosphorylation of they have potent mitogenic activity in intestinal epithelium.
Rb-1 releases p53, which activates other genes leading to cel- IGF II appears to be critical for embryonic development.
lular proliferation.
Almost all growth factors of the GI tract exert paracrine Fibroblast Growth Factor and Platelet-Derived
effects. However, many growth factors also possess autocrine
and even intracrine actions. It has become apparent that Growth Factor
growth factors and other signaling molecules secreted into the At least 7 related fibroblast growth factors (FGFs) have been
lumen of the gut can have important local biological actions. identified.180 These peptides have mitogenic effects on various
Distant effects of growth factors found in the circulation may cell types, including mesenchymal cells, and likely play an
important role in organogenesis and neovascularization.181 glucagon secretion, and delays gastric emptying. GIP stimu-
Although not unique to the GI tract, PDGF is one of the most lates insulin secretion when glucose levels are elevated and
thoroughly studied growth factors. It is important for fibro- decreases glucagon-stimulated hepatic glucose production.187
blast growth, and its receptor is expressed in the liver and On ingestion of a meal, glucose, as it is absorbed, stimulates
throughout the GI tract, where it appears to promote wound GLP-1 and GIP secretion. Circulating glucose then stimulates
healing. beta cell production of insulin, and this effect is substantially
augmented by incretins acting in conjunction with glucose to
increase insulin levels.
Trefoil Factors Postprandial hyperglycemia may also be controlled by
Trefoil factors (pS2, spasmolysin, and intestinal trefoil factor, delaying the delivery of food from the stomach to the small
which are also known as TTF1, 2, and 3, respectively) are a intestine, allowing the rise in insulin to keep pace with the rate
family of proteins expressed throughout the GI tract.182 They of glucose absorption. Several gut hormones that delay gastric
share a common structure, having 6 cysteine residues and 3 emptying have been shown to reduce postprandial glucose
disulfide bonds, creating a cloverleaf appearance that stabi- excursions (Box 4-2).185 Amylin (islet amyloid polypeptide) is
lizes the peptide within the gut lumen. The pS2 peptide is a 37–amino acid peptide synthesized primarily in the beta
produced in the gastric mucosa, spasmolysin is found in the cells of the pancreatic islets together with insulin. Although it
antrum and pancreas, and intestinal trefoil factor is produced was originally recognized for its ability to form amyloid
throughout the small and large intestines. These peptides are deposits in association with beta cell loss, it has more recently
produced by mucous neck cells in the stomach or goblet cells been found to suppress glucagon secretion, delay gastric emp-
in the intestine and are secreted onto the mucosal surface of tying, and induce satiety.188 Insulin resistance in obese patients
the gut. It is likely that trefoil factors act on the apical surface is associated with increased levels of both insulin and amylin.
of the epithelial cells, where they have growth-promoting Type 2 diabetes mellitus is characterized by high circulat-
properties on the GI mucosa. ing insulin levels and insulin resistance. In addition, insulin
Other peptides signaling through GPCRs may also have levels do not increase appropriately after a meal, and signifi-
growth-promoting effects. Three important examples include cant hyperglycemia occurs, which is consistent with an
gastrin, CCK, and gastrin-releasing peptide (GRP). Gastrin impaired incretin effect. GIP secretion is preserved in type 2
stimulates the growth of enterochromaffin-like cells of the diabetes, but the insulinotropic effect of GIP is reduced.189
stomach and induces proliferation of the oxyntic mucosa con- Although the precise cause is unknown, the defect in GIP-
taining parietal cells.183 Gastrin binds to CCK-2 receptors of stimulated insulin release is most pronounced in the late
the stomach and activates PLC and Ras pathways, which ulti- phase of insulin secretion. In contrast to GIP, GLP-1 secretion
mately results in activation of protein kinase C and MAP is reduced in insulin-resistant type 2 diabetics. The lower
kinase, respectively. MAP kinase, which can also be activated GLP-1 levels are caused by impaired secretion rather than
by tyrosine kinase receptors typical of growth factors, causes increased degradation of the hormone.190 Unlike GIP, the
the phosphorylation of transcription factors that are involved insulin response to infusion of GLP-1 is preserved, indicating
in cellular proliferation. In some cells, cAMP and protein that the beta cell can respond normally to this incretin hormone.
kinase A exert synergistic effects on cellular growth through These observations suggest that GLP-1 administration could
activation of nuclear transcription factors such as cAMP- be a viable treatment for the hyperglycemia associated with
responsive element binding (protein) (CREB). However, in diabetes.191 The growing evidence that beta cell failure may
other cells, cAMP antagonizes proliferation. Therefore, develop in type 2 diabetes supports the use of incretin hor-
depending on the cell type, the effects of growth factors such mones, such as GLP-1, or agents that delay GLP-1 degradation
as EGF, IGF, and PDGF may be enhanced by hormones that by the enzyme dipeptidyl peptidase-4 (DPP-4) to enhance beta
stimulate cAMP production. Certain colon cancer cells possess cell function.192,193 Several incretin analogs are now used clini-
CCK-2 receptors and respond to the proliferative effects of cally for the treatment of diabetes.194
gastrin. Moreover, gastrin may be produced by some colon
cancers, enabling it to exert an autocrine effect to promote
cancer growth.184 Whether circulating gastrin initiates colon
cancer development is unknown. BOX 4-2 GI Peptides That Regulate Postprandial Blood
Glucose Levels
Diabetes Mellitus and the Gastrointestinal Tract Stimulate Insulin Release
GI hormones play an important role in the regulation of Glucagon-like peptide-1
insulin secretion and glucose homeostasis. These hormones Glucose-dependent insulinotropic peptide
control processes that facilitate the digestion and absorption Gastrin-releasing peptide
of nutrients, as well as disposal of nutrients that have reached Cholecystokinin (potentiates amino acid–stimulated insulin
the bloodstream. In particular, gut peptides control postpran- release)
dial glucose levels through 3 different mechanisms: (1) stimu- Gastrin (in presence of amino acids)
lation of insulin secretion from pancreatic beta cells, (2) Vasoactive intestinal peptide (potentiates glucose-stimulated
inhibition of hepatic gluconeogenesis by suppression of glu- insulin release)
Pituitary adenylate cyclase-activating peptide (potentiates
cagon secretion, and (3) delaying the delivery of carbohy-
glucose-stimulated insulin release)
drates to the small intestine by inhibiting gastric emptying.185
Motilin
Each of these actions reduces the blood glucose excursions
that normally occur after eating. Delay Gastric Emptying
Approximately 50% of the insulin released after a meal is Cholecystokinin
the result of GI hormones that potentiate insulin secretion.186 Amylin
This interaction is known as the enteroinsular axis, and the gut Secretin
peptides that stimulate insulin release are known as incretins.
Inhibit Glucagon Release
The major incretins are GLP-1 and GIP. GLP-1 not only stimu- Amylin
lates insulin secretion but also increases beta cell mass, inhibits
Gastrointestinal Regulation of Appetite indicating that PYY3-36 signals satiety through this receptor.200
PYY3-36 has been shown in humans to decrease hunger scores
During a meal, ingested nutrients interact with cells of the and caloric intake.201 Interestingly, most of the GI peptide
mouth and GI tract. Endocrine cells of the stomach and small receptors involved in satiety are also found in the brain, where
intestine possess receptors that are linked to the secretion of they mediate similar satiety effects. This may represent con-
GI hormones. GI peptides are then released into the surround- servation of peptide signals that serve similar purposes.
ing space, where they exert paracrine actions or are taken up Leptin is referred to as an adiposity signal because it is
into the circulation, where they function as hormones.195 Each released into the blood in proportion to the amount of body
of these transmitters facilitates the ingestion, digestion, fat and is considered a long-term regulator of energy balance.
absorption, or distribution of nutrients that are essential for Together with CCK, leptin reduces food intake and produces
the organism. Some GI hormones control the size of an a greater reduction in body weight than either agent alone.129
ingested meal and are known as satiety signals. Satiety hor- Therefore, it appears that long-term regulators of energy
mones share several qualities.196 First, they decrease meal size. balance can affect short-term regulators through a decrease in
Second, blocking their endogenous activity leads to increased meal size, which may promote weight reduction.
meal size. Third, reduction of food intake is not the result of Hunger and initiation of a meal are intimately related.
an aversion to food. Fourth, secretion of the hormone is caused Ghrelin is intriguing because it is the only known circulating
by ingestion of food that normally causes cessation of eating GI hormone that has orexigenic effects.145 Produced by the
(Table 4-2). Most satiety signals interact with specific receptors stomach, ghrelin levels increase abruptly before the onset of a
on nerves leading from the GI tract to the hindbrain. meal and decrease rapidly after eating, suggesting that it
CCK is one of the most extensively studied satiety hor- signals initiation of a meal. Consistent with this role are studies
mones. In a time- and dose-dependent manner, CCK reduces demonstrating that administration of antighrelin antibodies or
food intake in animals and humans,197 an effect that is medi- a ghrelin receptor antagonist suppresses food intake.202 It is
ated by CCK-1 receptors residing on vagus nerve endings.198 not known if ghrelin is responsible for the hunger pains and
The effect of CCK on food intake is a proved physiologic audible bowel sounds that occur in people who are hungry.
action, because administration of a CCK receptor antagonist Bariatric surgery, in particular Roux-en-Y gastric bypass, is
induces hunger and results in larger meal sizes. CCK also the most effective procedure for long-term weight loss in
delays the rate at which food empties from the stomach, which morbid obesity. Although it had been assumed that weight
may explain why the satiety actions of CCK are most apparent loss accompanying this procedure was the result of reduced
when the stomach is distended. Together, these findings indi- gastric capacity and calorie malabsorption, recent evidence of
cate that CCK provides a signal for terminating a meal. reduced ghrelin release and exaggerated PYY release after a
GLP-1 is produced by enteroendocrine cells in the ileum meal has suggested that hormonal factors may contribute to
and colon and is released in response to food in the intestine. reduced calorie intake.203
Although the primary action of GLP-1 is to stimulate insulin
secretion, it also delays gastric emptying. Moreover, infusion
of GLP-1 increases satiety and produces feelings of fullness,
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THE GASTROINTESTINAL LUMEN Histamine

brown fat thermogenesis in rats. PLoS One 2012;

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