Introduction to Endocrinology

Obert Tada

Department of Livestock and Wildlife Management Midlands State University

Contents

Definitions Hormones as Chemical Messengers & Regulators Vertebrate Endocrine Glands & Associated Hormones Classification of Hormones Chemical, Functional, Source,Radius of action Signal Transduction & Mode of Action Control of Hormone Action Feedback Systems

Introduction

Sub-discipline of the broader field physiology.

Concerned with chemical mediation or hormones.

Regulation by hormones tends to be slower and sustained.

Serves to maintain homeostasis (a condition of constancy).

HISTORICAL PERSPECTIVE OF THE SCIENCE OF ENDOCRINOLOGY

The first recorded endocrine experiment was published by Berthold in 1849.

Berthold castrates a cockerel (male chicken), wattles and male-specific behaviour didn’t develop.

If replaced development is restored If transplant only one testis, it hypertrophies.

In 1889 Von Mering and Minkowski demonstrated: ablation of dog pancreas: elevated blood sugar levels suggested that diabetes mellitus might result from a defect of carbohydrate metabolism due to the lack of pancreatic function.

Later, in 1922, Banting and Best demonstrated that the Islets of Langerhans in the pancreas produced a substance that lowers blood glucose (insulin).

first critical experiment done in 1902 by Baylis & Starling.

discovered a substance secreted by mucosa of SI that stimulates flow of pancreatic juice (secretin).

Starling (1905) introduced the term

hormone (

Greek -arouse to activity).

Definition

Classical:

Chemical substances produced by specialized ductless glands that are released in the blood and carried to other parts of the body to produce specific regulatory effects.

Many hormone-like substances don't meet criteria Prostaglandins, Growth Factors, Etc.

Broader Definition:

Physiological Chemical Regulators

Modes of Transmission

Endocrine:

gland to blood to target, classical mode.

Exocrine:

secreted through duct to "exterior" of body, which can be urinary, reproductive, or digestive tract lumen.

Paracrine:

cell to cell, interstitial fluid.

Autocrine:

cell to itself, interstitial fluid.

Neurocrine:

involving nerve cells, synapse or into blood stream.

Epicrine:

cell to cell, without going into body fluids, gap Junctions.

Intracrine:

cell to itself, without going into body fluids

Ectocrine

: Ectohormones, may be transported by water or by air.

Pheromone

: functions within a species.

Allelochemical

: functions between two different species

Neurocrine:

Release of chemical mediators by neurons including neurosecretion (neurohormones released into bloodstream), neurotransmitters (synaptic transmission), neuromodulators (released into synaptic cleft, no effect alone but modify the responsiveness of postsynaptic or presynaptic neuron).

Characteristics of a hormone

Organic chemical agent Liberated by living cells of an organism in a restricted area Liberated into a vascular system or tissue fluid.

Is generally effective at some distance from the source Results in the coordination of parts of the organism.

Act at very low concentrations: picogram to nanogram per ml concentrations in blood (parts per billion or trillion) Have short half lives in blood Degraded after action on target, disallows further and/or unnecessary action, & half life increased by glycosylation (sialic acids) Regulate intracellular biochemical reactions at targets Usually involved in some type of secretory action of a cell The distant site of action is referred to as the

target tissue

. The target tissue has

specific receptors

for the hormone (only that particular hormone can bind).

PROBLEMS WITH THE CLASSICAL DEFINITION

Hormones are not necessarily produced by ductless glands can be secreted by small groups of cells or even by individual cells Secretion of an endocrine gland/cell is not unihormonal. multiple active secreted substances are produced by a cell Most hormones have multiple production sites Hormones are not secreted only into the bloodstream.

can be released into lymph or extra-cellular fluids, therefore not always blood-borne Hormones do not always have distant target sites.

can act in paracrine or even autocrine fashion Hormone action cannot be stereotyped.

varies according to the nature and state of the target site, may be determined by the expression of receptors in the target cell

PHYSIOLOGICAL PROCESSES CONTROLLED BY HORMONES

Growth Trophic effects Development and tissue differentiation Lactation Reproduction Osmoregulation (salt/water balance) Thermoregulation Metabolism Blood composition Behaviour Molting Muscle contraction Stress response Pigmentation Feeding

THE CLASSICAL VERTEBRATE ENDOCRINE SYSTEM

Two divisions

Neuroendocrine System

: have neurosecretory nerve terminals which release contents into blood or extracellular fluid.

Peripheral Endocrine System

: present only in higher invertebrates and vertebrates. comprised of non-neural tissue • no direct link to the nervous system

NEUROENDOCRINE SYSTEM

Hypothalamus Pituitary/ Hypophysis Pineal gland

Hypothalamus

produces release and release-inhibiting factors that influence secretion of anterior pituitary hormones. most are peptides but some are biogenic amines (amino acid derivatives).

The hypothalamus is a neuro-endocrine area which acts as a "transducer" to convert neuronal activity into hormonal secretions.

it is like the "head ganglion" of the autonomic nervous system.

it is especially concerned with cardiovascular, respiratory, GI, and reproductive control.

it exhibits pulsatile, circadian, and sex cycle rhythms in its secretion.

it is associated with emotions such as fear, rage, aversion, pleasure, and reward.

The Releasing Hormones (or, Releasing Factors)

A. Somatotropin Releasing & Inhibiting Factors

& somatostatin, or SRF & SRIF) SRIF inhibits both STH and PRL secretion. (Somatocrinin SRIF/somatostatin also inhibits TRH.

B. Prolactin Releasing & Inhibiting Factors

(PRF & PIF)

C. Thyrotropin Releasing & Inhibiting Hormone

TIH) (TRH &

D. Gonadotropin Releasing & Inhibiting Hormone

GnIH) (GnRH &

E. Corticotropin Releasing & Inhibiting Hormone

CIH) stimulates the secretion of ACTH and MSH.

(CRH &

Neurohypophyseal Extension Of The Hypothalamus

Oxytocin

(PIT) it stimulates mammary and uterine smooth muscle contractions.

Vasopressin

(Antidiuretic Hormone(ADH)) it promotes the collecting ducts and distal tubules in the renal nephrons to reabsorb water.

Pituitary/ Hypophysis

Located ventral to the brain, posterior to the optic chiasma. Attached to the brain by a stalk (infundibulum).

"Master Gland" since many important hormones are secreted from pituitary

Adenohypophysis & Neurohypophysis

1. Adenohypophysis (anterior pituitary) 2. Neurohypophysis (posterior pituitary)

Posterior Pituitary

Oxytocin

Milk letdown Uterine Contractions

ADH

Fluid Balance

Synthesized in hypothalamus, secreted by the posterior pituitary/neurohypophysis

Anterior Pituitary/Adenohypophysis

pituitary hormones are peptides. synthesis & secretion of anterior pituitary hormones is modulated by Releasing and/or Inhibiting Factors from the hypothalamus.

Examples: • GnRH  LH and FSH Release • Dopamine/Prolactin Inhibiting Factor  Prolactin Inhibition

Anterior Pituitary/Adenohypophysis

A.

Growth Hormone (GH) or Somatotropin (ST)

a. Acts on all tissues that can grow, Long Bones b. Metabolic Effects • i. Increase Protein Synthesis • ii. Increase Fatty Acid Mobilization • iii. Decrease Glucose Uptake c. Mediated by Somatomedins from liver • Also called insulin-like growth factors (IGFs)

B. Adrenal Corticotropic Hormone (ACTH)

Acts on Adrenal Cortex to stimulate steroidogenesis • Glucocorticoids • Mineralocorticoids

Anterior Pituitary/Adenohypophysis

C. Prolactin (PRL)

Acts on Mammary Gland Luteotropic agent (rodents) Maternal Behavior?

D. Thyroid Stimulating Hormone (TSH)

Acts on Thyroid to release thyroid hormones

E. LH and FSH

Acts on Gonads Reproductive Functions

F. Melanocyte Stimulating Hormone (MSH)

Skin Pigmentation

The Pineal Gland

located just behind the hypothalamus innervated by sympathetic neurons.

gland synthesizes and secretes melatonin. Melatonin secreted mainly during the night. many potential functions suggested for melatonin that it is difficult to itemize biological effects on reproduction and it promotes sleep (and hibernation).

reportedly delays puberty, reduces gonadal steroidogenesis, and suppresses ovulation.

regulates the secretion of ACTH, corticosterone, b endorphin, PRL, renin, ADH, oxytocin, GH, & LH.

Pineal Gland

>

Melatonin

may also regulate the manifestation of psychosis, expression of depression, and aggression and anxiety.

are also reports that it acts as an anti-oxidant, delaying aging and reducing cancer???

has been suggested that it may express its physiological functions and refine life by modulating the synthesis and actions of serotonin and serotonin receptors.

Secretes melatonin, serotonin and other tryptophan derivatives.

Controls seasonal breeders.

PERIPHERAL ENDOCRINE SYSTEM

Thyroid gland

: consists of follicles.

located on Trachea Thyroid Hormones amines Thyroxine (T4), and Triiodothyronine (T3) Increase Oxygen Consumption by Cells Increase Metabolism

Adrenal Gland

(two parts)

Located cranial to the kidney Adrenal cortex hormones ( steroids ) intermediary metabolism, osmoregulation, development A. Glucocorticoids (Cortisol) Increase Glucose Biosynthesis Increase Diuresis Anti-inflammatory B. Mineralocorticoids (Aldosterone) Increase Na+ reabsorption Increase K+ excretion

Adrenal medulla

Adrenal medulla hormones amines adrenal chromaffin tissue produces catecholeamines A. Epinephrine (Adrenaline) Increase Metabolism B. Norepinephrine Increase Metabolism Neurotransmitter (Sympathetic)

Gonads

- testicles

A. Androgens ( Testosterone and DHT)

Produced by Leydig (Interstitial) Cells Stimulated by LH.

Functions: causes differentiation of the fetal male reproductive tract and testicular descent maintains libido (sex drive) maintains secretory activity of the accessory glands development of male genital duct system and maintain spermatogenesis, after initiated by FSH.

mainly act on skeletal muscle (protein anabolic steroids).

stimulate erythropoiesis of blood stem cells in bone marrow.

Testicles cont’d

develop and maintains secondary sex characteristics, e.g., shoulder girdle, vocal cords, hair growth, musculature, plumage in birds, skin coloration in reptiles) and sex accessory structures (seminal vesicles, prostate, penis).

behaviour.

B. Peptide Hormones

Produced by Sertoli cells Inhibin Feedback on pituitary to decrease FSH Activin Feedback on pituitary to increase FSH Androgen Binding Protein maintain Androgens in Testis

Gonads --Ovary

A. Estrogen

Produced primarily by Follicle Mostly under control of FSH Functions: Stimulate endometrial gland growth Stimulate duct growth in the mammary gland Increase secretory activity of the reproductive ducts Initiation of sexual receptivity Regulation of LH and GnRH by the anterior pituitary and hypothalamus Early union of the epiphysis with the shafts of long bones, ceasing growth of long bones Bone Maintenance

Estrogen cont’d

Protein anabolism Vaginal epithelium proliferation and cornification Differentiation of genital duct system (after specification - lack of androgen, MIH).

Development of sex accessory organs (clitoris, labia).

Liver - yolk proteins (vitellogenesis - lower vertebrates).

Corpus luteum - luteolytic.

CNS differentiation.

Secondary sex characteristics (mammary gland development).

Protein anabolic (uterus, mammary; note that androgen is the more important protein anabolic hormone in skeletal muscle).

Water balance - cause eodema, all subcutaneous tissues.

Ca++ metabolism - enhances deposition in bone (prevents osteoporosis.) Thymus (decreases size)

Progesterone

Produced by Follicle and Corpus Luteum.

Mostly under control of LH.

Functions: i. Promotion of endometrial gland growth.

ii. Stimulation of secretory activity of the oviduct and endometrial glands to provide nutrients for the developing embryo prior to implantation.

iii. Promotion of alveolar growth in the mammary gland (with estrogen).

iv. Prevention of contraction of the uterus during pregnancy.

Peptide Hormones Inhibin Activin Others Gonadal Steroid and Peptide Hormones

responsible for feedback regulation of Hypothalamic-Pituitary-Gonadal Axis

Prostaglandins

derived from Arachidonic Acid produced by almost all tissues Functions: Luteolytic agent (PGF2alpha) Decrease Gastric Secretion Relax Bronchial Smooth Muscle Decrease Platelet Aggregation (PGI2) Increase Platelet Aggregation (Thromboxane A2) Vasoconstriction (PGF2alpha)

Pancreas

an exocrine and endocrine organ.

Islets of Langerhans

exocrine tissue is dispersed among the located behind stomach between duodenum and spleen Endocrine Function from Islets of Langerhans Alpha Cells—Glucagon Beta Cells—Insulin Delta Cells—Somatostatin

Pancreatic Hormones (Peptides)

Insulin

Increase glucose transport into cells Production of glycogen in liver Increase Lipogenesis Increase protein synthesis Decrease Blood Glucose

Glucagon

Increase Blood Glucose • Reverse effects of insulin Increase insulin and somatostatin

Somatostatin

Slows nutrients into circulation Moderates metabolic effects by insulin, glucagon, and GH Also hypothalamic inhibiting factor for somatotropin,

Parathyroids

located near or embedded in Thyroid.

produce Parathormone or Parathyroid Hormone (PTH) peptide hormone.

hypercalcaemic increases blood calcium by increasing bone resorption, increase renal tubular resorption, and Ca ++ uptake from gut by stimulating Vitamin D synthesis (1,25 dihyrdoxycholecalciferol) from vitamin D precursors by the kidney Increase Ca ++ and PO 4 ++ absorption by intestine.

Parafollicular/C-Cells of Thyroid

found in discrete structure in lower vertebrates the Ultimobranchial gland.

Calcitonin (CT)

hypocalcaemic

decreases blood Ca ++ in gut.

by inhibiting Ca ++ uptake increasing bone mineralization.

increases Calcium loss by kidney.

Gastrointestinal tract

referred to as the diffuse neuro-endocrine system.

has neuron-like cells.

Stomach Gastrin

• Stimulated by food • Causes release of HCl and digestive enzymes from stomach.

• Increases gastric motility

GIT cont’d

Small Intestines A. Secretin

• Causes pancreas to secrete bicarbonates to buffer acidic intestine contents • Inhibit Gastric Activity • Stimulates Gall bladder

B. Cholecystokinin (CCK)

• Causes pancreas to release digestive enzymes • Inhibit Gastric Activity • Stimulates Gall bladder

OTHER ORGANS WITH ENDOCRINE FUNCTION

Liver A. Angiotensin II

• Regulates Fluid balance

B. Insulin-like Growth Factors

• Mediates Growth Hormone Action • Initiates lactation

Others.

Kidneys

A. Erythropoietin Low Oxygen stimulates Stimulates bone marrow to produce new RBCs B. Renin Released during low blood pressure Initiates Angiotensin II from liver C. Vitamin D Activated by PTH Promotes Ca++ absorption from intestine

Brain and Heart

Brain

:

Neuro-steroids Peptides biogenic amines.

Heart

:

Atrial Natriuretic Factor (ANF) from atria.

diuretic, induces salt and water excretion.

Placenta

A. Steroid Hormones

Estrogen Progesterone

B. Peptides

Chorionic Gonadotropins • Pregnancy maintenance and diagnosis Relaxin • Softening of Pubic symphysis Placental Lactogens • Immune function • Fetal Growth • Initiation of Lactation

Thymus

Located in the upper thorax above the heart and in front of the aorta.

In humans and other mammals, the thymus begins atrophy shortly after puberty.

Play a pivotal role in the development of immunological competency.

Thymosin and Thymopoietin T-lymphocyte production Cell-mediated immunity

Growth Factors

peptides produced by many organs and tissues besides growth these factors have many physiological activities Common Growth Factors Insulin-like Growth Factors (IGF) Epidermal Growth Factors (EGF) Fibroblast Growth Factors (FGF) Platelet-Derived Growth Factors (PDGF)

GENERAL CLASSES OF HORMONES

PEPTIDE/PROTEIN HORMONES

receptors in plasma membrane, except T 3 Amines & other small hormones: • many neurotransmitters & T • epinephrine and norepinephrine, • acetylcholine, dopamine, and serotonin, • other tyrosine derivatives (e.g., thyroxine).

4 .

Peptides: • TRH, endorphin & enkephalins, oxytocin & ADH Proteins: ( insulin)

LIPID SOLUABLE HORMONES

receptors in nucleus, or cytoplasm • Steroids, Thyroid hormones & Prostaglandins

HORMONE SECRETION

Hormones are packaged within secretory vesicles except thyroid and steroid hormones.

Stimulation of hormone secretion usually involves an exocytotic process in which the vesicles fuse with the plasma membrane and are actively extruded (involving ATP and Ca ++ ions) from the cell.

Exocytosis is often initiated when tropic hormones interact with target cell membrane receptors and promote membrane depolarization (or, hyperpolarization usually reduces exocytosis).

peptide/protein hormones are oftentimes secreted as pro-hormones.

steroid/thyroid hormones diffuse freely across the phospholipid bilayer of the plasma membrane.

HORMONE DELIVERY

Endocrine

= when the hormone travels through the blood to the target cells.

Paracrine

= when the hormone travels locally thru interstitial fluids to the target cells.

Autocrine

= when the hormone travels locally and self stimulates.

Neuro-endocrine

= when a neuro-hormone travels thru the blood to target.

Neurocrine

= when a neurotransmitter travels across a synapse to stimulate postsynaptic cell.

HORMONE METABOLISM

Amines

such as catecholamines are inactivated in the liver and at synapses.

Peptides

are mainly inactivated by blood, liver, and kidney proteases.

Steroids

, usually protected by plasma proteins, are metabolized in the liver.

Thyroxines

are deiodinated in many different tissues.

There is evidence of internalization of some hormones and membrane receptors.

MECHANISMS OF HORMONE ACTION

All peptide hormones and neurotransmitters act on membrane receptors.

this may lead to depolarization, or to hyperpolarization.

this appears to always lead to phosphorylation reactions (kinase).

this appears to always lead to gene expression.

All steroid hormones and thyroxines act on intracellular receptors.

This usually leads to gene expression.

MECHANISMS cont’d

interaction btwn a hormone & its specific receptor on target tissue results in the physiological response of the hormone location of hormone receptors Plasma membrane Cytoplasm Nucleus Nos. of receptors on a target cell can change As cell changes in developmental or differentiation states By up-regulation By down-regulation

Membrane receptors

Used by peptide, amino acid, or fatty acid hormones Receptor binding causes activation of 2 nd messenger system cAMP cGMP Tyrosine kinase Ca ++ Cascade of enzyme reactions eventually causes activation of transcription factors to stimulate (or inhibit) transcription of mRNA from DNA.

Nuclear (and cytoplasmic) receptors

Primarily steroid hormones Thyroid Hormone (amine), Vit. A and D also belong to this family Lipophilic steroid diffuse though plasma (and nuclear) membranes where they bind to a specific receptor in the cytoplasm or nucleus All steroids have nuclear receptors Not all steroid hormones have cytoplasmic receptors Receptor binding causes a conformational change that allows the hormone-receptor complex(es) to interact with nuclear chromatin as a transcription factor Whether hormone-receptor complex interacts with the nuclear chromatin as a monomer or dimer may effect

INTERACTION BETWN HORMONES & MEMBRANE RECEPTORS

Receptors provide the specificity for hormone-cell interaction.

At normal physiological levels, each hormone interacts with its own specific cellular receptor.

In most cells, a maximal biological response is achieved when only a small percentage (e.g.,

1%

) of receptors is occupied.

There are

four major classes of receptors

: receptors that are also enzymes (sometimes span the membrane only once).

receptors coupled to (i.e., part of) ion gates.

receptors associated with G (GTP-binding) proteins.

receptors with unknown transduction mechanisms.

Receptors cont’d

Most receptors for hormones are large proteins that span the plasma membrane 7 times.

the majority of receptors for peptide hormones and neurotransmitters are linked to G-proteins.

Receptors are formed by the usual transcription and translation processes (i.e., like any protein).

Receptors are extraordinarily dynamic molecules (i.e., they change their shape, location, etc.) Ligand/receptor coupling initiates membrane signal transduction processes by causing conformational changes in the receptor upon its phosphorylation, or auto-phosphorylation.

HORMONE ACTION: SIGNAL TRANSDUCTION

G-PROTEINS

(guanidine triphosphate binding proteins) ligand/receptor coupling usually activates GTP-binding proteins.

G-proteins function to transfer the hormone signal to enzyme (i.e., kinase) effectors and/or ion channels.

G-proteins are a class of highly homologous heterotrimeric proteins.

The trimers are composed of  -,  -, and  -subunits.

Activated receptors enzymatically activate G-proteins.

one receptor can act on several G-proteins

G-Protein cont’d

G-protein activation involves replacement of GDP on the  -subunit with GTP (i.e., phosphorylation), and with dissociation of the  -subunit from the  dimer.

Usually the  -subunit determines the kind of cytosolic reaction  -dimers can also carry signals for effector functions and their interaction with Mg ++ is important.

Activation of  -subunits cause one or more of the following events: activation of adenylate cyclase  cAMP formation  protein kinase A (PKA).

activation of phospholipase C (PLC) and phospholipase A 2 (PLA 2 ).

indirect activation of ion channels in the plasma membrane.

G-Protein Cont’d

a number of diff. categories of G-proteins: G s -proteins, which stimulate adenylate cyclase and activate Ca ++ channels and activate PKA.

G i -proteins, which inhibit adenylate cyclase and activate K + channels and inactivate PKA.

G q -proteins, which activate PKC and PLA 2 .

G o -proteins, which activate both Ca especially in neurons.

++ and K + channels, a single receptor can activate several G-protein molecules.

ACTIVATION OF ADENYLATE CYCLASES AND cAMP

There are a number of different adenylate cyclases (ACs): (a) types I and VIII cyclases appear to be primarily associated with neurons, (b) type III may be restricted to olfactory neuroreceptors, and (c) types II, IV, V, & VI are expressed ubiquitously.

Adenylate cyclases catalyzes ATP to cAMP.

cAMP is rapidly metabolized to AMP by phosphodiesterases.

cAMP releases regulatory subunits to activate protein kinase A (PKA).

NB: Phosphorylation can sometimes inactivate enzymes.) cAMP can stimulate certain steroid synthesis, such as progesterone synthesis.

cAMP also is associated with the gating of ion channels.

cAMP is inactivated by ligands that couple with G i -proteins.

MEMBRANE PHOSPHOLIPIDS & THE PHOSPHOLIPASES

PHOSPHOLIPASE-C AND HYDROLYSIS OF PHOSPHOINOSITIDES

Some receptor-associated G-proteins can activate phospholipase C, a hydrolytic enzyme specifically acting on phospholipids.

PLC hydrolyzes membrane phosphatidylinositol 4,5-biphosphate (PIP 2 ) to form two bioactive products, namely diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP 3 ).

DAG is a membrane bound diglyceride that (with help from Ca ++ ) activates PKC.

IP 3 ER.

is a cytosol soluble 6-carbon sugar that releases Ca ++ from the

MEMBRANE PHOSPHOLIPIDS & THE PHOSPHOLIPASES

CALCIUM IONS AND THE FORMATION OF A PROTEIN KINASE

Ca ++ serves as a special "second messenger" to activate another protein kinase: Cytosolic Ca ++ increases not only by the action of IP 3 on the ER, but also by ion gating at the plasma membrane and influx from the extracellular fluids.

action of cytosolic Ca ++ calmodulin.

is mediated by a Ca ++ -binding protein Calmodulin undergoes a conformational change in the presence of Ca ++ .

This leads to activation of a calmodulin-dependent protein kinase (K cam ).

SUMMARY OF PKA, PKC, AND K

cam

FORMATION AND ACTION

Kinases regulate phosphorylation.

Phosphorylation processes involve the flow of energy via phosphate bonds in an organized pattern through a number of effector enzymes and regulatory proteins that are sequentially energized to undergo conformational changes that cause characteristic cell responses.

Phosphorylation is a reversible covalent reaction.

Kinases primarily phosphorylate serine & threonine, along with tyrosine & serine amino acids.

Kinases usually span the membrane , or are on its inner surface.

Kinases are sometimes referred to as "third messengers" in signal transduction processes.

EFFECTS OF SIGNAL TRANSDUCTION ON ION GATING

One of the principal effects of G-protein-mediated signal transduction is the gating of ion channels in the plasma membrane.

One established example of this ion gating is when cAMP dependent protein kinase (i.e., PKA) phorphorylates Ca ++ channels and promotes a rapid influx of this ion into the cell.

TERMINATION OF SIGNAL TRANSDUCTION PROCESSES

Like most biological processes, hormonal activation of G-protein coupled receptors cannot proceed indefinitely.

Occasionally, the termination of signaling is brought about by dissociation of the hormone (ligand) from its receptor.

However, there are other built-in mechanisms to terminate (sometimes quite rapidly) the signaling process that is initiated by the interaction of hormones with G-protein-coupled receptors.

A. GTPase-ACTIVATING PROTEINS

Termination of G-protein signaling usually occurs when the  subunit reassociates with the  -subunit.

This recombination of G-protein entities can occur naturally, albeit slowly, by

GTPase activity

that is intrinsic to the  -subunit.

The GTPase converts GTP into GDP on the  -subunit, and thereby allows reunion with the  -subunit.

TERMINATION OF SIGNAL TRANSDUCTION PROCESSES

B. UNCOUPLING AND SEQUESTRATION OF MEMBRANE RECEPTORS

G-protein-coupled hormone receptors are dynamic molecules that are inactivated mainly by internalization into the cytoplasm of the cell.

once internalized, the receptor can be either recycled back to the plasma membrane to respond to additional agonist, or it can be degraded (i.e., hydrolyzed) by lysosomal activity. "short term" inactivation of the receptors occurs, usually within seconds, when they become phosphorylated and affect G proteins in the local area.

SECRETION AND ACTION OF ADENOHYPOPHYSEAL HORMONES

Somatotropin (SH) (AKA = growth hormone (GH), somatotropic hormone (STH)) GH & PRL are both alpha-helical polypeptide chains of 191 amino acids.

Somatocrinin (a somatotropin-releasing hormone) from the hypothalamus may promote GH secretion.

Secretion of GH increases under deep sleep, stress, high estrogen, low blood glucose, or protein depletion.

Most of the daily secretion is during the first 90 min of sleep.

GH increases the size of skeletal, muscle, and connective tissues.

Growth Hormone cont’d

GH acts by stimulating protein synthesis in these tissues within 30 min.

its action is also associated with formation of DNA, RNA, and ribosomes.

GH acts opposite to insulin in that it limits glucose utilization by body cells and stimulates fat mobilization.

GH secretion is inhibited by somatostatin (also known as SRIF, or somatotropin release inhibiting factor), which increases with obesity, elevated fatty acids, and glucocorticoid stimulation.

Prolactin (PRL)

a.k.a lactogen, lactogenic hormone, mammotropin) A hypothalamic-releasing factor for PRL has not been identified (TRH, may promote its release.) PRL secretion may be controlled by a pituitary inhibitory substance, i.e., PIF, from the hypothalamus; or, quite possibly by hypothalamic dopamine, a simple derivative of tyrosine.

PRL was first characterized for its ability to initiate lactation.

stimulates receptors in mammary glandular cells to take up glucose and synthesize fat, casein, lactalbumin, and lactose.

PRL decreases within 3 weeks after parturition if the mother does not nurse.

The Glycoprotein Hormones

Thyrotropin (a.k.a, thyroid stimulating hormone, or TSH) TSH stimulates the thyroid gland to secrete T 3 and T 4 .

TSH is controlled by: CNS input to the hypothalamus to secrete thyrotropin releasing hormone (i.e., TRH), T 3 and T 4 feedback inhibition of TRH secretion, and T 3 and T 4 secretion).

feedback inhibition of thyrotropes (and TSH

Luteinizing Hormone (LH, or lutropin)

LH stimulates: progesterone synthesis, ovulation, and luteinization of the female ovarian follicles, and it also stimulates testosterone production by the interstitial cells of the male gonads.

LH production is regulated by hypothalamic GnRH, which decreases in response to high circulating levels of sex steroids such as progesterone.

At menarche, there is a rapid rise in GnRH and thus LH secretion.

At menopause, there is an even greater rise in LH secretion.

Follicle Stimulating Hormone (FSH, or follitropin)

FSH stimulates follicle growth in the ovary and spermatogenesis in the testes.

FSH is regulated by GnRH, regulated by blood steroids.

FSH has sexual cycle rhythms in the female and circadian rhythms in the male.

The Stress-Related Hormones

Proopiomelanocortin (POMC)

a common prohormone produced by cells of the anterior and intermediate lobes.

fragments of this prohormone make ACTH, MSH, b -endorphin, & enkephalins.

Endorphins and enkephalins Corticotropin (ACTH, or adrenocorticotropic hormone)

ACTH stimulates adrenal cortex to secrete glucocorticoids.

ACTH production is regulated by: CNS activity from stress impulses to the hypothalamus (increasing CRF), ACTH feedback to hypothalamus, glucocorticoid reduction of CRF production by the hypothalamus glucocorticoid suppression of corticotrope secretion of ACTH.

HORMONAL CONTROL OF CALCIUM HOMEOSTASIS

Ca ++ is involved in control systems throughout the body. (70 kg animal has 1 kg Ca ++ .) Ca ++ is actively transported across the intestinal mucosa and renal tubules.

In plasma & fluids it is kept at 10 mg/100 ml --50% is free and 50% is albumin bound.

Bone is the principal storage depot for Ca ++ .

THE NATURE OF BONE, BONE MINERALS, AND BONE CELLS

Bone is constantly being formed, absorbed, and redeposited throughout life.

The two principal bone minerals are Ca ++ & PO 4 = , which is involved in cAMP, ATP, and phosphorylation. (renal regulation) Ca ++ and PO 4 = in high concentration precipitate to form hydroxyapatite in bone.

osteoclasts are most active in bone resorption and remodelling.

osteoclasts secrete acids to promote release of Ca ++ PO 4 = .

&

Types of bone cells

The four types of bone cells are:

Precursor (osteogenic) cells

, which resemble fibroblasts, and form other cells.

Osteoblasts

collagen) and polysaccharides that form the soft organic part of bone tissue.

which synthesize and secrete the proteins (mostly • osteoblasts are most active in bone formation and redeposition.

• osteoblasts cause alkalinity that promotes hydroxyapatite precipitation.

Osteocytes

, which are transformed osteoblasts that have "buried" themselves in collagen and bone matrix, except for canaliculi through which they remain in contact with cytoplasmic processes of other osteocytes and osteoblasts.

Osteoclasts

are giant multinucleated cells that reabsorb bone (by lysosomal enzymes) and release Ca ++ . (derivatives of large lymphocyte/macrophage)

Factors That Control Ca

++

Homeostasis

A. The Parathyroid Glands And Parathyroid Hormone

The chief cells secrete PTH. Low levels of circulating Ca ++ mediated mechanism.

increases PTH exocytosis via a cAMP PTH functions to: increase the number of osteoclasts.

couple with receptors on osteoclasts to increase cAMP and PLC (IP3 and DAG).

• These signal transduction events increase osteoclast activity and acid secretions from osteoclasts.

enhance intestinal uptake of Ca ++ .

increase renal proximal tubular resorption of Ca ++ .

increase PO 4 = ionization).

excretion across the proximal tubule (favors Ca ++ stimulate biosynthesis of 1-25-dihydroxy vitamin D3 by the kidneys.

B. Skin, And The Formation Of Active Vitamin D

3

Epidermal cells (in the skin) secrete a provitamin D (7-dehydrocholesterol) into the extracellular spaces.

UV radiation converts this into vitamin D3 (cholecalciferol).

In the liver, this is converted by 25-hydroxylase to 25-OH vitamin D3.

In the kidney, this is converted by 1a -hydroxylase to 1a ,25-(OH) 2 D 3 .

Low blood Ca ++ vitamin promotes PTH which stimulates renal 1a -hydroxylase.

Functions of Vitamin D3: It increases absorption of Ca ++ large intestine).

and PO 4 = across the GI tract (mainly the Promotes CaBP (after 2 hours) to facilitate the active transport of Ca ++ across intestines acts synergistically with PTH to cause bone demineralization when circulating Ca ++ is low.

It may promote renal resorption of Ca ++ and PO 4 = .

"C" Cells Of The Thyroid Glands And Calcitonin Secretion

The "C" (clear) cells develop as parafollicular cells among the thyroid follicles.

High blood Ca ++ causes "C" cells to release membrane-bound granules of calcitonin (CT).

Gastrin, and to a lesser extent CCK, stimulates CT (in anticipation of Ca ++ with food).

The functions of CT include: prevention of hypercalcemia by promoting bone deposition.

altering the morphology of osteoclasts • causing them to loose their ruffled borders and decreasing their lysosomal enzyme secretions.

CT is high during gestation and lactation, to protect maternal bones.

CT may inhibit the hypothalamic hunger center, or stimulate the satiety center, since it decreases food intake in rats and monkeys.

OTHER PANCREATIC HORMONE & METABOLIC REGULATION

PANCREATIC POLYPEPTIDE SECRETION

(PP) (the "hunger" hormone) slight hypoglycemia increases PP secretion markedly (via vagal activity).

Glucose infusions suppress PP secretion, but meals tend to increase PP.

Esp. protein meals and AAs stimulate PP secretion.

ACTION & RESPONSE

suppresses SS secretions from gut and pancreas.

inhibits gall bladder secretion and pancreatic enzyme secretion.

might stimulate the hunger center.

Paracrine Effects Of The Pancreatic Hormones

Insulin inhibits glucagon secretion in order to preserve stored nutrients.

Glucagon stimulates insulin and SS to facilitate utilization of new nutrients.

Somatostatin inhibits both insulin and glucagon secretion.

Pancreatic polypeptide has unknown paracrine action.

GROWTH HORMONES AND GROWTH FACTORS

Mammalian cells have characteristic growth cycles: "G 0" "G 1" is the resting stage.

is a growth phase preparatory to the synthetic phase (S).

"S" is the synthetic phase when DNA is duplicated.

"G 2" is a short period (3-4 hours) when protein synthesis occurs before mitosis.

"M" is the complex phase of mitosis.

Daughter cells may: re-enter the cycle (e.g., stem cells of bone, GI epithelial cells, spermatogonia) become dormant (resting) (e.g., fibroblasts, osteocytes, memory cells of immunity.

become fully mature cells (e.g., skeletal muscle cells, neurons, RBCs, PMNs, spermatozoa).

GROWTH HORMONES AND GROWTH FACTORS

Hormones are the principal stimulant for tissue and organ growth (hypertrophy/atrophy).

Principal control point is probably at the transition from G o to G 1 .

Growth of tissue may occur as a result of: cell enlargement (hypertrophy) cell multiplication (hyperplasty) intercellular secretions (e.g., formation of extracellular matrix)

GH, Somatomedins, Insulin, Prolactin, Placental Lactogen, Nerve Growth Factor, Epidermal Growth Factor, Platelet-Derived Growth Factor, Angiogenesis Factors, Erythropoietin, Thymosin.

Somatotropin And The Somatomedins

secreted from the pituitary upon stimulation by somatocrinin (SS inhibits) STH is essential for normal growth in humans and most vertebrates.

STH causes growth of the epiphyseal regions of the long bones.

STH acts indirectly by producing sulfation factor(s) from liver = somatomedins.

Somatomedins (i.e., somatotropin-mediating agents) are growth factors with insulin-like properties:

Somatotropin And The Somatomedins

Somatomedin molecular structure similar to insulin these growth factors are protected in the plasma by carrier proteins.

IGF-I and IGF-II have peptide sequences related to insulin.

their receptors are structurally related to the insulin receptors however, insulin stimulates metabolic effects on glucose metabolism and cell differentiation.

whereas, the growth factors promote cell proliferation and multiplication. the actions of these somatomedins is mainly on bone and connective tissues.

By negative feedback, IGF-I stimulates hypothalamic SS, & inhibits STH.

Insulin & Prolactin

although insulin is known for its action on intermediary metabolism, it also has profound effects on growth processes.

Insulin is required for the full anabolic effects of STH it provides glucose & AAs.

PRL and STH are structurally similar so PRL has growth effects.

Diff. is that PRL is usually associated with reproductive tissue growth.

along with its effect on mammary tissue it affects growth and function of gonads.

Placental Lactogen (PL)

Syncytiotrophoblastic cells produce chorionic somatomammotropin which promotes lactogenic activity, and therefore is called placental lactogen.

PL & STH both have 191 AAs, which are identical throughout 85% of their structure.

PL increases during the last half of pregnancy.

Nerve Growth Factor

promotes nerve differentiation and growth.

interacts with nerve plasma membrane, is internalized, and transported toward nerve cell body by retrograde axonal transport.

is essential for normal growth and life-long function of sympathetic post-ganglionic neurons, secrete norepinephrine.

stimulates synthesis of tyrosine hydroxylase and dopamine hydroxylase to promote catecholamines.

In mice, it increases adrenal medulla, promotes aggressive behavior, & defense.

In mice, it is under the control of testosterone & thyroxine (10X more in male).

It has been reported that infusion of NGF into the brains of rats counteracts learning deficiencies.

OTHER PEPTIDE GROWTH FACTORS

Epidermal Growth Factor (53 AAs)

enhances cell proliferation in basal layer of skin (tooth eruption, eye opening).

suggested that licking wounds introduces EGF to promote skin proliferation.

Platelet-Derived Growth Factor

released from a granules of platelets during blood clotting.

at site of injury, it may promote contraction of injured vessels to reduce flow.

it may also promote conversion of fibroblasts to myofibroblasts to aid in wound healing and in the formation of new arterial walls. (angiogenesis).

Growth Factors That Promote Angiogenesis

Fibroblast growth factor promote angiogenesis and mitosis in epithelia, mesenchyme (i.e., skeletal, circulatory, immune, and connective tissues) & neurons.

have roles in development, neuron maintenance, and wound healing.

Transforming growth factor good in antibiotic creams to promote wound healing.

inhibits proliferation of most cells except for fibroblasts. (an example of a chalone???) Vascular endothelial cell growth factor growth factor that is important in angiogenesis.

Erythropoietin (EP) & Thymosin

This erythrocyte-stimulating factor has properties of a growth factor.

Its release from kidney (and liver) is promoted by tissue hypoxia.

EP enhances proliferation of erythrocyte precursor cells in bone marrow.

EP promotes the synthesis of 2.3 million RBCs/sec.

EP is a sialoprotein (sialic acid),containing 40% carbohydrate.

Thymosin

is secreted by the thymus it stimulates maturation of immune cells.