mechanisms of hormone action-module6

7/27/2019 Mechanisms of Hormone Action-module6

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Hormone Receptors

• Hormones are present at very low concentrations inthe extracellular fluid, generally in the atto- to

nanomolar range (10 –15 to 10 –9 mol/L).

• This concentration is much lower than that of the

many structurally similar molecules (sterols, amino

acids, peptides, proteins) and other molecules that

circulate at concentrations in the micro- to millimolar

(10 –6

to 10 –3

mol/L) range.• Target cells, therefore, must distinguish not only

between different hormones present in small

amounts but also between a given hormone and the

106- to 109-fold excess of other similar molecules.



• This high degree of discrimination is provided bycell-associated recognition molecules called

receptors.

• Cells respond to a hormone when they express aspecific receptor for that hormone.

• The hormone binds to the receptor resulting in theactivation of a signal transduction mechanismthat ultimately leads to cell type-specificresponses.

• Receptor numbers and type vary greatly indifferent target tissues, providing one of the major determinants of specific cellular responses tocirculating hormones.



• For example, ACTH receptors are located almost

exclusively in the adrenal cortex, and FSH receptors

are found only in the gonads.

• In contrast, insulin and TRs are widely distributed,

reflecting the need for metabolic responses in all

tissues.



• Receptors for hormones are divided into twomajor classes:

membrane and

nuclear • Membrane receptors primarily bind peptide

hormones and catecholamines.

• Nuclear receptors bind small molecules that can

diffuse across the cell membrane, such as TH,

steroids, and vitamin D.



Cell-surface receptor proteins

(Membrane Receptors) and

Mechanism of Action

• Proteins, peptides, catecholamines and eicosanoidsinitiate a response by binding to a receptor located in

the plasma membrane

• The mechanism of action of this group of hormones

can best be discussed in terms of the intracellular

signals they generate.

• These signals include cAMP (cyclic AMP; a nucleotide

derived from ATP through the action of adenylcyclase; cGMP, a nucleotide formed by guanylyl

cyclase; Ca2+; and phosphatidylinositides).



• Such molecules are termed as secondmessengers

• Many of these second messengers affect gene

transcription but they also influence a variety of other biologic processes.



Structure of Cell Surface Receptors

• Extracellular domains

• Transmembrane domains

• Cytoplasmic or intracellular domains



Subclasses of membrane

receptors:

1. G Protein –

Coupled Receptors (GPCR) • Are also called Serpentine receptors or 7

transmembrane segment (7tm) receptors.

• These receptors typically have seven hydrophobic

plasma membrane-spanning domains.

• Receptors of this class signal through guanine

nucleotide-bound protein intermediates.

• To date, hundreds of G protein –linked receptor geneshave been identified; this represents the largest family

of cell surface receptors in humans.

• A wide variety of responses are mediated by theGPCRs.



G-protein receptors activate trimeric G-protein

Activated G-protein alters the cellular concentration

of a “second messenger”: usually cyclic AMP or

Ca2+

The second messenger activates a protein kinase

enzyme

The protein kinase phosphorylates another enzyme

and alters its activity



• Trimeric G-proteins disassemble when activated:

Inactive G-protein has a bound GDP

When activated: GDP dissociates, new GTP is

boundThis causes a to dissociate from bg

a binds to adenylate cyclase, altering its activity

Gs protein stimulates & activates adenylate cyclase,Gi inhibits it



• Gs and Gi are under the influence of differenthormones.

• Hormones that induce GTP binding to Gi cause

inhibition of adenylyl cyclase, resulting in lower cellular [cAMP].

• Gq subunits couple to phospholipase C,

generating diacylglycerol and inositol

triphosphate, leading to activation of proteinkinase C and the release of intracellular calcium.



Inositol –

phospholipid signaling pathway:

Binding of a ligand to its transmembrane receptor

(R) activates the G protein (Gq)

This in turn stimulates a specific membrane-bound phospholipase C (PLC), which catalyzes

hydrolysis of the phospholipid PIP2 in the inner

leaflet of the plasma membrane.

The resulting second messengers, IP3 anddiacylglycerol (DAG), are responsible for carrying

the signal to the interior of the cell



IP3 diffuses to the endoplasmic reticulum,where it binds to and opens a Ca2+channel

in the membrane, releasing stored Ca2+

Diacylglycerol remains in the plasmamembrane, where it—along with Ca2+

activates the enzyme protein kinase C

(PKC).



Sutherlandwon a Nobel

Prize for this

work in 1971.



2. Gated ion channels

• The excitability of sensory cells, neurons, and

myocytes depends on ion channels, signal

transducers that provide a regulated path for themovement of inorganic ions such as Na+ ,K+, Ca2+ and

Cl- across the plasma membrane in response to

various stimuli.

• Ion channels are ―gated‖; they may be open or closed,depending on whether the associated receptor has

been activated by the binding of its specific ligand (a

neurotransmitter, for example) or by a change in the

transmembrane electrical potential, Vm.



3. Receptor Enzymes• A fundamentally different mechanism of signal

transduction is carried out by the receptor enzymes.

• These proteins have a ligand-binding domain on the

extracellular surface of the plasma membrane and an

enzyme active site on the cytosolic side, with the two

domains connected by a single transmembrane

segment.• Commonly, the receptor enzyme is a protein kinase

that phosphorylates Tyr residues in specific target

proteins; the insulin receptor is the prototype for this

group.



• Other receptor enzymes synthesize theintracellular second messenger cGMP in

response to extracellular signals.

• The receptor for atrial natriuretic factor istypical of this type.



Insulin receptor

• The insulin receptor has two types of subunits, α

and β. The α-subunit is on the extracellular side of

the membrane, and it binds to insulin. The β-subunit spans the membrane.

• When insulin binds to the α-subunit, the β-

subunits autophosphorylate on tyrosine residues.

• These then phosphorylate target proteins calledinsulin receptor substrates (IRS).

• These IRSs act as the second messengers in the

cell.



Nuclear Receptors and

Mechanisms of Action

• The family of nuclear receptors has grown tonearly 100 members, many of which are still

classified as orphan receptors because their

ligands, if they exist, remain to be identified.

• Though all nuclear receptors ultimately act to

increase or decrease gene transcription, some

(e.g., glucocorticoid receptor) reside primarily in

the cytoplasm, whereas others (e.g., thyroidhormone receptor) are always located in the

nucleus.



• After ligand binding, the cytoplasmically localizedreceptors translocate to the nucleus.

• Activated receptor binds to regulatory DNA

sequences called Hormone Response Elementsand initiates transcription of the target gene



General mechanism by which steroid and thyroid

hormones, retinoids, and vitamin D regulate gene

expression.

mechanisms of hormone action-module6

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