Hormones travel via the bloodstream to target cells

The endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

A cell is a target because is has a specific receptor for the hormone

Most hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

Principal functions of the endocrine system

Maintenance of the internal environment in the body (maintaining the optimum biochemical environment).
Integration and development.

regulation

of

growth

and

Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn.

Types of cell-to-cell signaling

Classic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

Response vs. distance traveled

Endocrine action: the hormone is distributed in blood and binds to distant target cells. Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood. Autocrine action: the hormone acts on the same cell that produced it.

Major hormones and systems

Top down organization of endocrine system. Hypothalamus produces releasing factors that stimulate production of anterior pituitary hormone which act on peripheral endocrine gland to stimulate release of third hormone
Specific examples to follow

Posterior pituitary hormones are synthesized in

neuronal cell bodies in the hypothalamus and are released via synapses in posterior pituitary.
Oxytocin and antidiuretic hormone (ADH)

Types of hormones
Hormones are categorized into four structural

groups, with members of each group having many properties in common:

Peptides and proteins

Amino acid derivatives

Steroids Fatty acid derivatives - Eicosanoids

Peptide/protein hormones
Range from 3 amino acids to hundreds of amino acids

in size. Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone. Peptide/protein hormones are water soluble. Comprise the largest number of hormones perhaps in thousands

Peptide/protein hormones
Are encoded by a specific gene which is transcribed into

mRNA and translated into a protein precursor called a preprohormone Preprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation) Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormone Prohormone is processed into active hormone and packaged into secretory vessicles

Peptide/protein hormones
Secretory vesicles move to plasma membrane where they

await a signal. Then they are exocytosed and secreted into blood stream In some cases the prohormone is secreted and converted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung

Peptide/protein hormone synthesis

Amine hormones
There are two groups of hormones derived from the amino acid tyrosine Thyroid hormones and Catecholamines

Thyroid Hormone
Thyroid hormones are basically a "double" tyrosine

with the critical incorporation of 3 or 4 iodine atoms. Thyroid hormone is produced by the thyroid gland and is lipid soluble Thyroid hormones are produced by modification of a tyrosine residue contained in thyroglobulin, posttranslationally modified to bind iodine, then proteolytically cleaved and released as T4 and T3. T3 and T4 then bind to thyroxin binding globulin for transport in the blood

Thyroid hormones

Catecholamine hormones
Catecholamines are both neurohormones and neurotransmitters.
These include epinephrine, and norepinephrine Epinephrine and norepinephrine are produced by

the adrenal medulla both are water soluble

Secreted like peptide hormones

Synthesis of catecholamines

Amine Hormones
Two other amino acids are used for synthesis of

hormones: Tryptophan is the precursor to serotonin and the pineal hormone melatonin Glutamic acid is converted to histamine

Steroid hormones
All steroid hormones are derived from cholesterol and

differ only in the ring structure and side chains attached to it. All steroid hormones are lipid soluble

Types of steroid hormones

Glucocorticoids; cortisol is the major representative

in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

Steroid hormones
Are not packaged, but synthesized and immediately released Are all derived from the same parent compound: Cholesterol Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells

Steroid hormones
Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins. Corticosteroid binding globulin carries cortisol Sex steroid binding globulin carries testosterone and estradiol In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

Steroids can be transformed to active steroid in target cell

Steroidogenic Enzymes
Common name
Side-chain cleavage enzyme; desmolase 3 beta-hydroxysteroid dehydrogenase 17 alpha-hydroxylase/17,20 lyase 21-hydroxylase 11 beta-hydroxylase Aldosterone synthase

"Old" name
P450SCC 3 beta-HSD P450C17 P450C21 P450C11 P450C11AS

Current name
CYP11A1 3 beta-HSD CYP17 CYP21A2 CYP11B1 CYP11B2

Aromatase

P450aro

CYP19

Steroid hormone synthesis

All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

Steroid hormone synthesis

The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins. Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated.

Extracellular lipoprotein Cholesterol pool

LH ATP cAMP

acetate

cholesterol PKA+
Pregnenolone

3bHSD

Progesterone Androstenedione

P450c17
17bHSD

TESTOSTERONE

1,25-Dihydroxy Vitamin D3
1,25-dihydroxy Vitamin D3 is also derived from

cholesterol and is lipid soluble Not really a vitamin as it can be synthesized de novo Acts as a true hormone

Fatty Acid Derivatives - Eicosanoids

Arachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell. These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds.

Fatty Acid Derivatives - Eicosanoids

Eicosanoids are a large group of molecules

derived from polyunsaturated fatty acids. The principal groups of hormones of this class are prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Regulation of hormone secretion

Sensing and signaling: a biological need is sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are:
receipt of stimulus synthesis and secretion of hormone delivery of hormone to target cell evoking target cell response degradation of hormone

Control of Endocrine Activity

The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial.

Control of Endocrine Activity

The concentration of hormone as seen by target cells is determined by three factors: Rate of production Rate of delivery Rate of degradation and elimination

Control of Endocrine Activity

Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits, as described below in more detail.

Control of Endocrine Activity

Rate of delivery: An example of this effect is blood flow to a target organ or group of target cells - high blood flow delivers more hormone than low blood flow.

Control of Endocrine Activity

Rate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes. Shutting off secretion of a hormone that has a very short half-life causes circulating hormone concentration to plummet, but if a hormone's biological half-life is long, effective concentrations persist for some time after secretion ceases.

Feedback Control of Hormone Production

Feedback loops are used extensively to regulate secretion of hormones in the hypothalamic-pituitary axis. An important example of a negative feedback loop is seen in control of thyroid hormone secretion

Inputs to endocrine cells

Neural control
Neural input to hypothalamus stimulates synthesis

and secretion of releasing factors which stimulate pituitary hormone production and release

Chronotropic control
Endogenous neuronal rhythmicity
Diurnal rhythms, circadian rhythms (growth hormone

and cortisol), Sleep-wake cycle; seasonal rhythm

Episodic secretion of hormones

Response-stimulus coupling enables the endocrine

system to remain responsive to physiological demands Secretory episodes occur with different periodicity Pulses can be as frequent as every 5-10 minutes

Episodic secretion of hormones

The most prominent episodes of release occur with a frequency of about one hourreferred to as circhoral An episode of release longer than an hour, but less than 24 hours, the rhythm is referred to as ultradian If the periodicity is approximately 24 hours, the rhythm is referred to as circadian
usually referred to as diurnal because the increase in

secretory activity happens at a defined period of the day.

Circadian (chronotropic) control

Circadian Clock

Feedback control
Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion
Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation

Negative feedback effects of cortisol

Substrate-hormone control
Glucose and insulin: as glucose increases it stimulates

the pancreas to secrete insulin

Feedback control of insulin by glucose concentrations

Hormone-Receptor interactions
Definition: a protein that binds a ligand with high affinity and low capacity. This binding must be saturuable.
A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action.

Agonist vs. Antagonist

Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently
Antagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger

intracellular signaling events

Hormone-receptor interactions
Hormone--receptor interaction is defined by an equilibrium constant called the Kd, or dissociation constant.
The interaction is reversible and how easily the hormone is displaced from the receptor is a quantitation of its affinity. Hormone receptor interactions are very specific and the Kd ranges from 10-9 to 10-12 Molar

Spare receptors
In most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell.
Examples:
insulin

stimulates maximum glucose oxidation in adipocytes with only 2-3% of receptors bound LH stimulates maximum testosterone production in Leydig cells when only 1% of receptors are bound

Spare Receptors
Maximum response with 2-3% receptor occupancy 97% of receptors are spare Maximum biological response is achieved when all of the receptors are occupied on an average of <3% of the time The greater the proportion of spare receptors, the more sensitive the target cell to the hormone Lower concentration of hormone required to achieve half-maximal response

Classes of hormones
The hormones fall into two general classes based on

their solubility in water.

The water soluble hormones are the catecholamines

(epinephrine and norepinephrine) and peptide/protein hormones. The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

Types of receptors
Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane.
These types of receptors are coupled to various second

messenger systems which mediate the action of the hormone in the target cell.

Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell.
Because these hormones can diffuse through the lipid

bilayer of the plasma membrane, their receptors are located on the interior of the target cell

Hormones and their receptors

Hormone Class of hormone Location Amine (epinephrine) Water-soluble Cell surface

Amine (thyroid hormone) Peptide/protein

Lipid soluble

Intracellular

Water soluble

Cell surface

Steroids and Vitamin D

Lipid Soluble

Intracellular

Second messenger systems

Receptors for the water soluble hormones are found on

the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell

Second messengers for cellsurface receptors

Second messenger systems include:
Adenylate cyclase which catalyzes the conversion of ATP

to cyclic AMP; Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides); Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

Types of receptors

Second messenger systems

Each of these second messenger systems activates a specific protein kinase enzyme.
These include cyclic nucleotide-dependent protein

kinases Calcium/calmodulin-dependent protein kinase, and protein kinase C which depends on diacyl glycerol binding for activation.

Protein kinase C activity is further increased by calcium which is released by the action of inositol phosphates.

Second messenger systems

The generation of second messengers and activation of specific protein kinases results in changes in the activity of the target cell which characterizes the response that the hormone evokes.
Changes evoked by the actions of second messengers are usually rapid

Signal transduction mechanisms of hormones

Activation of adenylate cyclase b-adrenergic LH, FSH, TSH, hCG Inhibition of adenylate cyclase a2-adrenergic Opioid Increased phosphoinositide turnover a1-adgrenergic Angiotensin II Tyrosine kinase activation

Insulin Growth factors (PDGF, EGF, FGF, IGF-1

Glucagon
Vasopressin- V2 ACTH

Muscarinic cholinergic M2

Muscarinic cholinergic M3
Vasopressin V1

Growth hormone
Prolactin

Cell surface receptor action

G-protein coupled receptors

Adenylate cyclase, cAMP and PKA

Amplification via 2nd messenger

Transmembrane kinase-linked receptors

Certain receptors have intrinsic kinase activity. These

include receptors for growth factors, insulin etc. Receptors for growth factors usually have intrinsic tyrosine kinase activity Other tyrosine-kinase associated receptor, such as those for Growth Hormone, Prolactin and the cytokines, do not have intrinsic kinase activity, but activate soluble, intracellular kinases such as the Jak kinases. In addition, a newly described class of receptors have intrinsic serine/threonine kinase activitythis class includes receptors for inhibin, activin, TGFb, and Mullerian Inhibitory Factor (MIF).

Protein tyrosine kinase receptors

Receptors for lipid-soluble hormones reside within the cell

Because these hormones can diffuse through the lipid

bilayer of the plasma membrane, their receptors are located on the interior of the target cell. The lipid soluble hormone diffuses into the cell and binds to the receptor which undergoes a conformational change. The receptor-hormone complex is then binds to specific DNA sequences called response elements. These DNA sequences are in the regulatory regions of genes.

Receptors for lipid-soluble hormones reside within the cell

The receptor-hormone complex binds to the regulatory

region of the gene and changes the expression of that gene. In most cases binding of receptor-hormone complex to the gene stimulating the transcription of messenger RNA. The messenger RNA travels to the cytoplasm where it is translated into protein. The translated proteins that are produced participate in the response that is evoked by the hormone in the target cell Responses evoked by lipid soluble hormones are usually SLOW, requiring transcription/translation to evoke physiological responses.

Mechanism of lipid soluble hormone action

Receptor control mechanisms

Hormonally induced negative regulation of receptors is

referred to as homologous-desensitization This homeostatic mechanism protects from toxic effects of hormone excess. Heterologous desensitization occurs when exposure of the cell to one agonist reduces the responsiveness of the cell any other agonist that acts through a different receptor. This most commonly occurs through receptors that act through the adenylyl cyclase system. Heterologous desensitization results in a broad pattern of refractoriness with slower onset than homologous desensitization

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