Insulin: hormone

 Peptides
 Ex: insulin
 Ex: parathyroid hormone
 Channel linked: ex serotonin
 Enzyme linked: Ex: insulin receptor- a tyrosine kinase & guanylate cyclases
 G protein: epinephrine

Question
 Hemmorrage is the loss of whole blood, which consists of 55-60% plasma. Without
new fluids entering the body, how can plasma volume be elevated toward normal
levels to maintain homeostasis?
 Kidneys respond directly to blood loss and retain water, perspiration
goes down, respiration slows a little bit, coagulation cascade begins,
reabsorb water from interstitial fluid
 What kind of chemical messengers are epinephrine and cortisol. What organs and
cells do they communicate with?
Messengers
 Common messengers & hormones: Vasopressin, serotonin, cAMP, insulin,
FSH/estrogen, VEGF, histamine, epo, Ils
 Cell communication: direct via gap junctions, indirect via messengers
 Gap junctions: formed by connexins, let ions and small mol pass directly
from one cell to another. Electrically couples cells.
Classification
 Function
 Paracrine: released by one cell into an area and received by cell in the
area (diffusion)
 Growth factors, clotting factors, cytokines, histamine (secreted by
mast cells)
 Autocrine
 Neurotransmitters: electric signal sent to axon, meet with
neurotransmitters in vesicles, will induce fusion of vesicles → dumping of
the molecules in the vesicles, acts locally
 Ex: acetylcholine is released by neurons that trigger contraction of
skeletal muscle
 Hormones: released into interstitial fluid, circulate through the blood, often
released by the organs of the endocrine system, can travel long
distances, relatively slow
 Ex: insulin, vasopressin
 Neurohormones: released by neurosecretory cells, vasopression or
ADH (hypothalamus to kidneys)
 A chemical messengers may belong to more than one functional class
 Ex: serotonin is a neurotransmitter & a hormone. More serotonin is
made by gut cells than any other. Serotonin could be a hormone,
or neurotransmitter, or have paracrine effects when released from
platelets
 Paracrine: amines, peptides/proteins, eiconasoids
 Neurotransmitters: amino acids, amines, peptides/proteins (all lipophobic)
 Hormone: amines, steroids, peptides, proteins
 Structure
 Amino acids: lipophobic, hydrophilic (external receptors, activate enzyme
cascades)
 Often neurotransmitters, synthesized by neurons
 Ex: glutamate & aspartate, & glycine (used in protein synthesis), GABA
 AA are obtained from diet but the 4 amino acids that funciton as
neurotransmitters must be synthesized within the neuron that will
secrete them
 Amines
 Tend to be lipophobic, hydrophilic except thyroid hormones
 Derived from amino acids
 NH2, catecholamines- catechol=6 carbon ring (dopamine, epinephrine,
norepinephrine), thyroid hormones, histamine, serotonin
 Dopamine and norepinephrine function as neurotransmitters,
epinephrine as a hormone
 Dopamine is the precursor for all other catecholamines so all the
catecholamine secreting cells have tyrosine B-hydroxylase and
dopa cecarboxylase
 Catecholamines & thyroid hormones all come from tyrosine
 Tyrosine → dopamine, epinephrine, norepinephrine
 2 tyrosine & iodine → thyroid hormones
 Tryptophan → serotonin
 Histidine → histamine
 Peptides/proteins: lipophobic, hydrophilic
 Formed by cleaving larger proteins (pro-hormones)
 Prepropeptide --> propeptide --> peptide
 Most abundant type of ligand
 Made of chains of amino acids
 Peptide ligand <50 aa, protein ligand >50 aa
 Ex: insulin
  Ex: parathyroid hormone
 Steroids: lipophilic, hydrophobic
 Internal receptors, activate genes directly, can find their way into the
plasma membrane without transporters
 Derived from cholesterol
 Function as hormones
 Ex: cortisol, aldestrone, testosterone (greasy)
 Can't be stored in the cell prior to release, diffuse out so steroid
hormones are synthesized on demand and are released immediately
 Synthesis catalyzed by enzymes in ER or mitochondria
 Eicosonoids : lipophilic, hydrophobic
 Prostaglandins (pain & inflammation) , leukotrienes (inflammatory
response), thromboxanes (blood clotting)
 Derived form arachidonic acid, 20 carbon fatty acid found in PM
phospholipids, involves enzyme Phospholipase A
 Cyclooxygenase pathway: prostaglandins, prostcylcins,
thrombaxanes
 Lipoxygenase pathway: leukotrines
 Also synthesized and released on demand
 Anti-inflmmation drugs like aspirin target enzymes involved in eicosonoid
synthesis but these also lower blood clotting
Class Chemical Location of Functional classification
Property receptors on
target
Amino acids Lipophobic Plasma Neurotransmitters
membrane
Amines Lipophobic Plasma Paracrines,
membrane neurotransmitters,
hormones
Peptides/proteins Lipophobic Plasma Paracrines,
membrane neurotransmitters,
hormones
Steroids Lipophilic Cytosol Hormones
Eicosonoids Lipophilic Cytosol Paracrines
Transport of chemical messengers
 Paracrine messengers (local) & neurotransmitters (release locally into synapse):
simple diffusion through interstitial fluid
 Hormones: travel through blood
 Hydrophilic hormones, released by exocytosis, soluble in plasma
 Hydrophobic hormones, secreted by diffusion, bind to carrier proteins
 Ex: albumin, binds many
 Steroid specific globulins (Ex: corticosteroid-binding globulin)
 But, hormones aren't always bio-available when bound
 Ex: free testosterone & testosterone + albumin is available but
testosterone + SHBG isn't
  Why use carrier proteins? Increases half life & solubility, especially with
lipophilic messengers

H-PR H + PR
 Hydrophobic hormones are transported in bound form but <1% dissolve
in plasma, equilibrium develops in the bloodstream
 Bloodborne messengers are degraded by the liver and excreted by the
kidneys
Signal transduction
 Regulated by ligand/receptor interactions: reversible, specific, concentration
sensitive
 As the concentration of messenger increases, proportion of bound receptors
increases until all receptors have messengers bound to them - 100% saturation
 At any given concentration of messenger, # of bound receptors will be more
when more receptors are present, and response is stronger
 At low messenger concentrations, up-regulation- inc in # of receptors,
becoming more responsive the messenger
 Down regulation: dec in # of receptors when messenger concentrations are
higher than normal
 Ex: tolerance for drugs bc drugs often bind to receptors, then receptors
down regulate their activity
 A messenger can bind ot more than one type of receptor which have different
affinities. Ex: epinephrine and norepinephrine can bind to adrenergic receptors
 A single cell may have multiple types of receptors. Ex: muscle cell: acetylcholine &
insulin
 Magnitude of cellular response depends on the concentration of the messenger,
the number of receptors per target, affinity of receptors for messenger
 A ligand that activates a receptor: agonist
 Once bound to receptor, mimics normal response
 Ex: morphine: opioid receptor agonist
 A ligand that inhibits receptor activity: antagonist
 Binding blocks normal target response
 Competes with the normal ligand
 Ex: naloxone, binds tighter, shoot morphine off
 Opioids
 There are many receptors that will bind to opioids
 Mu opioid receptor: located on the membrane of neuronal cells
 GPCR: seven spanner, almost all senses operate by GPCRs
 Morphine and all opioids bind to the GPCR mu opioid receptor which
induces conformational change on the 3 g proteins which affect the brain
reward/pain system
 Two major treatments: stadol (partial agonist) and naloxone (antagonist,
very high affinity for the receptor), methadone (full agonist-might
antagonize the addiction but make you still fell good)
 Intracellular receptors
 Lipophilic messengers have their receptors inside the cells (slow, effects last
long time)
  Ex: steroid or thyroid hormone
 Crosses the membrane, binds to steroid hormone receptor
 If the receptor is in the nucleus, hormone goes diffuses into the nucleus
& binds to it forming the hormone receptor complex. If the receptor is in
the cytosol, it binds there, forming hormone receptor complex that then
enters the nucleus.
 In the nucleus HRC functions as a transcription factors by binding to HRE
 HRE: hormone response element, part of the promoter, recruit RNA
polymerase, gene expression.
 Coactivators: promote transcription (acetyltransferases)
 Corepressors: repress transcription (histone deacteylases)
 Steroid hormones
 Receptors for steroid hormones are nuclear receptors
 Two steroid hormones need to dimerize and bind to HRE
 Membrane bound receptors
 Channel-linked (ligand gated)
 Bring in ions
 Receptor and channel are the same protein, action is direct
 Change in transport of ions through the channel causes a FAST response
 Serotonin is an example. SSRI's enhance serotonin receptor signaling
 Ex: calcium channels enable calcium ions to enter the cell (which
normally are in very low amounts inside the cell), responses like secretion
of products, muscle contraction, change in protein activity. Ca can also be
a 2nd messenger, bind to calmodulin to form a complex which activates a
kinase
 Enzyme-linked
 Most immune receptors
 Cascade of enzymatic reactions inside a cell
 Kinases: phosphorylate
 Receptor and enzyme can part of the same protein. Ligand binding
activates the enzyme. Action can be direct and indirect.
 Phosphate can change the shape of a protein which can change
enzymatic activity and phosphates once bound can be recognized by
other proteins. Many proteins in our body have a motif that fits on
phosphates.
 Ex: insulin receptor- a tyrosine kinase & guanylate cyclases (GTP to
cGMP)
 G-protein coupled (memorize)
 Interact with g-proteins that then generate new second
messengers
 Effectors include ion channels & enzymes
 Doesn't stay active very long bc it also hydrolyzes GTP
 Activate G-proteins
 3 basic types
 those affecting ion channels (slow). Differs from fast ligand
gate channels in that G-protein linked channels can be
opened or closed whereas ligand gated channels open.
 Slower to open than ligand gated but stay on for longer than
ligand gated.
 stimulatory G proteins & inhibitory G proteins (activate &
inhibit downstream enzymes, amplifier enzymes)
 Common secondary messengers: cAMP, cGMP, inositol
triphosphate, diacylglycerol, calcium
 Epihenphrine will activate adenylate cyclase, camp, protein kinase
A (memorize)
 Messenger binds to receptor which is associated with a G
protein with alpha, beta, gama subunits and GDP is boudn to
alpha.
 GDP is exchanged for GTP
 Alpha subunit with GTP binds to adenylate cyclase which
then makes ATP into cAMP, which activates protein kinase A
by binding to inhibitory portion and releases the PKA
 Protein kinase A will phosphorylate proteins which lead to a
response
 Adenylate cyclase: makes ATP cyclic and gets rid of 2
phosphates
 Some of the stuff they do is go into nucleus and cause new
genes to be transcribed
 *** cAMP is degregaded by a phosphodiesterase
 Epinephrine vasopressin ACTG and glucagon work this way
 Ex: cholera acts on a G protein that overstimulates adenylate
cyclase, which enhances secretion of chloride ions --> diarrhea
 Two main types of cell responses: movement of ions, phosphorylation of
enzymes
Organ systems that communicate across distances
 Endocrine
 Signals (hormones) sent through blood
 Communicates through hormones which alters protein synthesis or activates G
proteins
 Slower than nervous system
 Pineal, hypothalamus, pituitary, thyroid, parathyroid, thymus, adrenal,
pancreas, ovary, testis
 Nervous
 Consists of neurons and glial cells
 Electric signals travel down axons
 Chemical signal b/w cells via the synapse
 Communication is fast & short lived (mostly ion channels)
Review
 Testosterone
 Cortisol
 Epinephrine
 Thyroid hormone
 Oxytocin
 Endogenous opioid
 Insulin