Phys Ch 74
Coordination of Body Functions by Chemical Messengers
 Chemical messenger systems
o Neurotransmitters – released by axon terminals of neurons into synaptic junctions and act locally to
control nerve cell functions
o Endocrine hormones – released by glands or specialized cells into circulating blood and influence
function of target cells at another location in body
o Neuroendocrine hormones – secreted by neurons into circulating blood and influence function of target
cells at another location in body
o Paracrines – secreted by cells into extracellular fluid and affect neighboring target cells of different type
o Autocrines – secreted by cells into extracellular fluid and affect function of same cells
o Cytokines – peptides secreted by cells into extracellular fluid and can function as autocrines, paracrines,
or endocrine hormones
 Include interleukins and lymphokines secreted by helper cells and act on other cells of immune
system
 Cytokine hormones like leptin produced by adipocytes sometimes called adipokines
 Neuroendocrine cells (located in hypothalamus) have axons that terminate in posterior pituitary gland and
median eminence and secrete several neurohormones, including ADH, oxytocin, and hypophysiotropic
hormones, which control secretion of anterior pituitary hormones
 Adrenal medullae and pituitary gland secrete hormones primarily in response to neural stimuli
 ACTH from anterior pituitary gland specifically stimulates adrenal cortex, causing it to secrete adrenocortical
hormones
 Placenta is additional source of sex hormones
Chemical Structure and Synthesis of Hormones
 3 general classes of hormones
o Proteins and polypeptides – include hormones secreted by pituitary glands, pancreas, parathyroid gland
o Steroids – secreted by adrenal cortex, ovaries, testes, and placenta
o Derivatives of amino acid tyrosine – secreted by thyroid and adrenal medullae
 No known polysaccharides or nucleic acid hormones
 In general, polypeptides with 10 or more amino acids called proteins, and those with less than 100 are peptides
 Protein and peptide hormones synthesized on rER of endocrine cells; usually synthesized as preprohormones
and are cleaved to form prohormones in ER; then transferred to Golgi apparatus for packaging into secretory
vesicles; enzymes in vesicles cleave prohormones to produce biologically active hormones and inactive
fragments; vesicles stored in cytoplasm (many bound to PM) until secretion needed
o Secretion of hormones and inactive fragments occurs when secretory vesicles fuse with PM and granular
contents extruded into interstitial fluid or directly into blood stream by exocytosis
o In many cases, stimulus for exocytosis is increase in cytosolic Ca2+ caused by depolarization of PM
o In other instances, stimulation of endocrine cell surface receptor causes increased cAMP and
subsequently activation of protein kinases that initiate secretion of hormone
o Peptide hormones water soluble, allowing them to enter circulatory system easily
 In most instances, steroid hormones synthesized from cholesterol itself; consist of 3 cyclohexyl rings and one
cyclopentyl ring combined into single structure
o Usually very little hormone storage in steroid-producing endocrine cells
o Large stores of cholesterol esters in cytoplasm vacuoles can be rapidly mobilized for steroid synthesis
after stimulus
o Much of cholesterol in steroid-producing cells comes from plasma; some de novo synthesis
o Diffuse across PM and enter interstitial fluid and then blood (no secretory vesicles)
 2 groups of hormones derived from tyrosine (thyroid and adrenal medullary hormones) formed by actions of
enzymes in cytoplasmic compartments of glandular cells
o Hormone secretion in thyroid occurs when amines split from thyroglobulin, and free hormones released
into blood stream; after entering blood, most combine with plasma proteins, especially thyroxinebinding globulin, which slowly releases hormones to target tissues
Gland/Tissue
Hormones
Major Functions
Hypothalamus
Thyrotropin-releasing hormone
(TRH)
Corticotropin-releasing hormone
(CRH)
Growth hormone-releasing
hormone (GHRH)
Growth hormone inhibitory
hormone (GHIH) (somatostatin)
Gonadotropin-releasing
hormone (GnRH)
Dopamine or prolactin-inhibiting
factor (PIF)
Growth hormone
Stimulates secretion of thyroid-stimulating hormone
(TSH) and prolactin
Causes release of adrenocorticotropic hormone
(ACTH)
Causes release of growth hormone
Anterior
pituitary
TSH
ACTH
Prolactin
FSH
LH
Posterior
pituitary
Antidiuretic hormone (ADH)
(also called vasopressin)
Oxytocin
Thyroid
Adrenal cortex
Thyroxine (T4) and
triiodothyronine (T3)
Calcitonin
Cortisol
Aldosterone
Adrenal
medulla
Pancreas
Norepinephrine, epinephrine
Insulin (β cells)
Glucagon (α cells)
Chemical
Structure
Peptide
Peptide
Peptide
Inhibits release of growth hormone
Peptide
Causes release of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH)
Inhibits release of prolactin
Amine
Stimulates protein synthesis and overall growth of
most cells and tissues
Stimulates synthesis and secretion of thyroid
hormones (thyroxine and triiodothyronine)
Stimulates synthesis and secretion of adrenocortical
hormones (cortisol, androgens, and aldosterone)
Promotes development of the female breasts and
secretion of milk
Causes growth of follicles in the ovaries and sperm
maturation in Sertoli cells of testes
Stimulates testosterone synthesis in Leydig cells of
testes; stimulates ovulation, formation of corpus
luteum, and estrogen and progesterone synthesis in
ovaries
Increases water reabsorption by the kidneys and
causes vasoconstriction and increased blood
pressure
Stimulates milk ejection from breasts and uterine
contractions
Increases the rates of chemical reactions in most
cells, thus increasing body metabolic rate
Promotes deposition of calcium in the bones and
decreases extracellular fluid calcium ion
concentration
Has multiple metabolic functions for controlling
metabolism of proteins, carbohydrates, and fats;
also has anti-inflammatory effects
Increases renal sodium reabsorption, potassium
secretion, and hydrogen ion secretion
Same effects as sympathetic stimulation
Peptide
Peptide
Peptide
Peptide
Peptide
Peptide
Peptide
Peptide
Amine
Peptide
Steroid
Steroid
Amine
Promotes glucose entry in many cells, and in this way Peptide
controls carbohydrate metabolism
Increases synthesis and release of glucose from the
Peptide
liver into the body fluids
Parathyroid
Parathyroid hormone (PTH)
Controls serum calcium ion concentration by
Peptide
increasing calcium absorption by the gut and kidneys
and releasing calcium from bones
Testes
Testosterone
Promotes development of male reproductive system Steroid
and male secondary sexual characteristics
Ovaries
Estrogens
Promotes growth and development of female
Steroid
reproductive system, female breasts, and female
secondary sexual characteristics
Progesterone
Stimulates secretion of "uterine milk" by the uterine Steroid
endometrial glands and promotes development of
secretory apparatus of breasts
Placenta
Human chorionic gonadotropin
Promotes growth of corpus luteum and secretion of
Peptide
(HCG)
estrogens and progesterone by corpus luteum
Human somatomammotropin
Probably helps promote development of some fetal
Peptide
tissues as well as the mother's breasts
Estrogens
See actions of estrogens from ovaries
Steroid
Progesterone
See actions of progesterone from ovaries
Steroid
Kidney
Renin
Catalyzes conversion of angiotensinogen to
Peptide
angiotensin I (acts as an enzyme)
1,25-Dihydroxycholecalciferol
Increases intestinal absorption of calcium and bone
Steroid
mineralization
Erythropoietin
Increases erythrocyte production
Peptide
Heart
Atrial natriuretic peptide (ANP)
Increases sodium excretion by kidneys, reduces
Peptide
blood pressure
Stomach
Gastrin
Stimulates HCl secretion by parietal cells
Peptide
Small intestine Secretin
Stimulates pancreatic acinar cells to release
Peptide
bicarbonate and water
Cholecystokinin (CCK)
Stimulates gallbladder contraction and release of
Peptide
pancreatic enzymes
Adipocytes
Leptin
Inhibits appetite, stimulates thermogenesis
Peptide
 Epinephrine and norepinephrine formed in adrenal medulla, which normally secretes 4x more epinephrine than
norepinephrine
o Catecholamines taken up into preformed vesicles and stored until secreted
o Catecholamines released from adrenal medullary cells by exocytosis
o Once catecholamines enter circulation, they can exist in plasma in free form or in conjugation with other
substances
Hormone Secretion, Transport, and Clearance from Blood
 Concentrations of hormones required to control most metabolic and endocrine functions incredibly small
 Although plasma concentrations of many hormones fluctuate in response to various stimuli that occur
throughout day, all hormones closely controlled, mostly through negative feedback mechanisms
o Controlled variable sometimes not secretory rate of hormone itself but degree of activity of target tissue
o Only when target tissue activity rises to appropriate levels will feedback signals to endocrine gland
become powerful enough to slow further secretion of hormone
 Positive feedback occurs in surge of LH that occurs as result of stimulatory effect of estrogen on anterior
pituitary before ovulation; secreted LH acts on ovaries to stimulate additional estrogen secretion, etc.
o Eventually, LH reaches appropriate concentration and typical negative feedback control exerted
 Periodic variations in hormone release influenced by seasonal changes, various stages of development and
aging, diurnal cycle, and sleep
o Secretion of GH markedly increased during early period of sleep but reduced during later stages of sleep
o Cyclical variations in hormone secretion due to changes in activity of neural pathways involved in
controlling hormone release

2 factors increase or decrease concentration of hormone in blood: rate of hormone secretion into blood and
rate of hormone removal from blood (metabolic clearance rate)
o Metabolic clearance rate = rate of disappearance of hormone from plasma/concentration of hormone
 Hormones are cleared from plasma by metabolic destruction by tissues, binding with tissues, excretion by liver
into bile, and excretion by kidneys into urine
o Hormones sometimes degraded at target cells by enzymatic processes that cause endocytosis of PM
hormone-receptor complex; hormone then metabolized in cell, and receptors recycled back to PM
 Most peptide hormones and catecholamines usually degraded by enzymes in blood and tissues and rapidly
excreted by kidneys and liver
o Half-life of circulation angiotensin II is less than a minute
Mechanism of Action of Hormones
 Receptors for hormones can be in nucleus, PM, or cytoplasm
o Receptors for protein, peptide, and catecholamine hormones in or on PM surface
o Primary receptors for different steroid hormones mainly in cytoplasm
o Receptors for thyroid hormones found in nucleus
 When hormone combines with receptor, this initiates cascade of reactions in cell, with each stage becoming
more powerfully activated so even small concentrations of hormone can have large effect
 Each receptor usually highly specific for single hormone
 Number of receptors in target cell always changing; receptor proteins often inactivated or destroyed during
course of function, and at times they are reactivated or new ones manufactured by protein-manufacturing
mechanism of cell
o Increased hormone concentration and increased binding with target cell receptors can cause
downregulation of receptors as a result of inactivation of some of receptor molecules, inactivation of
some of intracellular protein signaling molecules, temporary sequestration of receptor to inside cell
away from site of actions of hormones, destruction of receptors by lysosomes after internalization, or
decreased production of receptors
o Upregulation done by increasing formation of receptor or intracellular signaling molecules by proteinmanufacturing machinery of target cell or greater availability of receptor for interaction with hormone
 Ion channel-linked receptors – virtually all neurotransmitter substances combine with receptors in postsynaptic
membrane; causes conformational change in receptor, usually opening or closing ion channel
o Altered movement of ions through channels causes subsequent effects on postsynaptic cell
o Most hormones that open or close ion channels do so indirectly by coupling with G protein-linked or
enzyme-linked receptors
 G protein-linked hormone receptors – some parts of receptor that protrude into cytoplasm (especially
cytoplasmic tail of receptor) coupled to G proteins that include 3 parts (α, β, and γ subunits)
o When ligand binds to extracellular part of receptor, conformational change in receptor activates G
proteins and induces intracellular signals that either open or close ion channels or change activity of an
enzyme in cytoplasm of cell
o G proteins bind guanosine nucleotides
o In active state, α, β, and γ subunits form complex that binds GDP on α subunit; when receptor activated,
it undergoes conformational change that causes GDP-bound trimeric G protein to associated with
cytoplasmic part of receptor and exchange GDP for GTP
 Displacement of GDP by GTP causes α subunit to dissociate from trimeric complex and associate
with other intracellular signaling proteins, which alter activity of ion channels or intracellular
enzymes (such as adenylyl cyclase or phospholipase C)
 Signaling event terminated when hormone removed and α subunit inactivates itself by
converting bound GTP to GDP; then α subunit recombines with β and γ subunits to form
inactive, membrane-bound trimeric G protein
o Some hormones couple to inhibitory G proteins (Gi proteins), and some couple to stimulatory G proteins
(Gs proteins)
 Enzyme-linked hormone receptors – when activated, function directly as enzymes or are closely associated with
enzymes they activate
o
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Enzyme-linked receptors pass through membrane only once; hormone-binding site on outside of PM
and catalytic or enzyme-binding site on inside
o When hormone binds to extracellular part of receptor, enzyme immediately inside PM activated (or
inactivated)
o Many enzyme-linked receptors have intrinsic enzyme activity, while others rely on enzymes closely
associated with receptor to produce change in cell function
Leptin receptor – enzyme-linked receptor; leptin is hormone secreted by fat cells and is important in regulating
appetite and energy balance
o Leptin receptor is member of cytokine family of receptors that don’t themselves contain enzymatic
activity but signal through associated enzymes
o One of signaling pathways occurs through tyrosine kinase of janus kinase (JAK) family JAK2
o Leptin receptor exists as dimer and binding of leptin to extracellular part of receptor alters
conformation, enabling phosphorylation and activation of intracellular associated JAK2 molecules
o Activated JAK2 molecules phosphorylate other tyrosine residues within leptin receptor-JAK2 complex to
mediate intracellular signaling
o Intracellular signals include phosphorylation of STAT proteins, which activates transcription by leptin
target genes that initiate protein synthesis
o Phosphorylation of JAK2 also leads to activation of MAPK and PI3K
o Some of effects of leptin occur rapidly as a result of activation of intracellular enzymes, whereas other
actions occur more slowly and require synthesis of new proteins
Widely used hormonal control of cell function is for hormone to bind with transmembrane receptor, which then
becomes activated enzyme adenylyl cyclase at end that protrudes to interior of cell
o Catalyzes formation of cAMP
For a few peptide hormones, such as ANP, cGMP serves as second messenger
Adrenal and gonadal steroid hormones, thyroid hormones, retinoid hormones, and vitamin D bind with protein
receptors inside cell; because they are lipid soluble, they cross PM and interact with receptors in cytoplasm or
nucleus
o Activated hormone-receptor complex binds with specific promoter sequence of DNA (hormone
response element) and either activate or repress transcription of specific genes
Intracellular receptor can activate gene response only if appropriate combination of gene regulatory proteins
present; many regulatory proteins tissue specific
cAMP as second messenger – binding of hormone with receptor allows coupling of receptor to G protein
o Hormones that use cAMP signaling include ACTH, angiotensin II (epithelial cells), calcitonin,
catecholamines (β receptors), CRH, FSH, glucagon, HCG, LH, PTH, secretin, somatostatin, TSH, and
vasopressin (V2 receptor, epithelial cells)
o Stimulation by adenylyl cyclase (membrane-bound enzyme) by Gs protein catalyzes conversion of small
amount of ATP to cAMP in cell; this activates cAMP-dependent protein kinase, which phosphorylates
specific proteins, triggering biochemical reactions that ultimately lead to cell’s response to hormone
o Once cAMP formed inside cell, it usually activates cascade of enzymes; only a few molecules of activated
adenylyl cyclase inside PM cause many more molecules of next enzyme to be activated, etc.
In epithelial cells of renal tubules, cAMP increases permeability to water
Some hormones activate transmembrane receptors that activate enzyme phospholipase C attached to inside
projections of receptors; enzyme catalyzes breakdown of phospholipids in PM, especially phosphatidylinositol
biphosphate (PIP2), into IP3 and DAG
o IP3 mobilizes Ca2+ from mitochondria and ER, and Ca2+ have their own second messenger effects, such as
smooth muscle contraction and changes in cell secretion
o DAG activates PKC, which phosphorylates large number of proteins, leading to cell’s response
 Lipid portion of DAG is arachidonic acid, which is precursor for prostaglandins and other local
hormones
2+
Ca entry may be initiated by changes in membrane potential that open Ca2+ channels or hormone interacting
with membrane receptors that open Ca2+ channels
o On entering cell, Ca2+ binds with calmodulin, which has 4 Ca2+ sites; when 3-4 of the sites have bound
Ca2+, calmodulin changes shape and initiates activation or inhibition of protein kinases
o
Activation of calmodulin-dependent protein kinases causes (via phosphorylation) activation or inhibition
of proteins involved in cell’s response to hormone
o Calmodulin activates myosin light chain kinase, which acts directly on myosin of smooth muscle to cause
smooth muscle contraction
o Troponin C similar to calmodulin in both function and protein structure
 Steroid hormone diffuses across PM and enters cytoplasm of cell, where it binds to receptor protein
o Combined receptor protein-hormone diffuses into or is transported into nucleus
o Combo binds at specific points on DNA strands in chromosomes, which activates transcription process of
specific genes to form mRNA
o mRNA diffuses into cytoplasm, where it promotes translation process at ribosomes to form new
proteins
 Aldosterone (secreted by adrenal cortex) enters cytoplasm of renal tubular cells, which contain specific receptor
protein (mineralocorticoid receptor)
o After 45 minutes, proteins appear in renal tubular cells and promote Na+ reabsorption from tubules and
K+ secretion into tubules
 T4 and T3 cause increased transcription by specific genes in nucleus; hormones first bid directly with receptor
proteins (activated transcription factors) in nucleus; control function of gene promoters
o Activate genetic mechanisms for formation of 100+ types of proteins, many of which are enzymes that
promote enhanced intracellular metabolic activity in virtually all cells in body
o Once bound to intranuclear receptors, thyroid hormones can continue to express their control functions
for days to weeks
Measurement of Hormone Concentrations in Blood
 Measure hormones with radioimmunoassay – antibody highly specific for hormone to be measured produced,
and a small quantity mixed with quantity of fluid containing hormone to be measured and mixed simultaneously
with appropriate amount of purified standard hormone that has been tagged with radioactive isotope
o Must be too little antibody to bind completely both radioactively tagged hormone and hormone in fluid
to be assayed; natural hormone in assay fluid must compete with radioactive standard hormone for
binding sties
o Quantity of each hormone that binds proportional to its concentration in assay fluid
o After binding has reached equilibrium, antibody-hormone complex separated from remainder of
solution, and quantity of radioactive hormone bound in complex measured by radioactive counting
o To make assay highly quantitative, radioimmunoassay procedure performed for standard solutions of
untagged hormone at several concentration levels and standard curve plotted
 ELISA used to measure almost any protein, including hormones; often performed on plastic plates that each
have 96 small wells, each coated with antibody (AB1) specific for hormone being assayed
o Samples or standards added to each well, followed by AB2 that is specific for hormone but binds to
different site of hormone molecule
o 3rd antibody (AB3) that recognizes AB2 added and coupled to enzyme that converts suitable substrate to
product that can be easily detected by colorimetric or fluorescent optical methods
o Because each molecule of enzyme catalyzes formation of many thousands of product molecules, even
small amounts of hormone molecules can be detected
o Use excess antibodies so all hormone molecules captured in antibody-hormone complexes; amount of
hormone present in sample or in standard proportional to amount of product formed
o Widely used in labs because
 It doesn’t employ radioactive isotopes
 Much of assay can be automated using 96-well plates
 Proved to be cost-effective and accurate method for assessing hormone levels