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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.
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• 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.
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• 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.
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• 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.
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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).
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• Such molecules are termed as secondmessengers
• Many of these second messengers affect gene
transcription but they also influence a variety of other biologic processes.
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Structure of Cell Surface Receptors
• Extracellular domains
• Transmembrane domains
• Cytoplasmic or intracellular domains
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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.
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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
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• 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
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• 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.
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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
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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).
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Sutherlandwon a Nobel
Prize for this
work in 1971.
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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.
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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.
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• Other receptor enzymes synthesize theintracellular second messenger cGMP in
response to extracellular signals.
• The receptor for atrial natriuretic factor istypical of this type.
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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.
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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.
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• 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
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