INTRACELLULAR SIGNALLING

KAMRAN
 INTRACELLULAR SIGNALING:
Signal Transduction
• Cell membranes, cytoplasm and even the cell nucleus, contain cell-
specific receptors for various ligands, which are involved in outside-
inside signaling, i.e. signal transduction
• Ligands include hormones, growth factors, cytokines, PGs and proteases
• Hormones are involved in a variety of metabolic processes that
maintain homeostasis, e.g. glucagon, insulin and the catecholamines
• GFs are involved in mitogenesis, whereas cytokines play critical roles in
the differentiation, proliferation and function of various cell lineages
• Interaction of such ligands with their membrane, cell-specific receptors
or intracellular receptors causes conformational changes in the receptor
and, in many instances receptor-associated cytoplasmic proteins
• Such events result in the initiation of a cascade of important, but as yet
incompletely understood, events leading to e.g. enzyme activation,
differentiation and/or cell division
 Molecular Biology of the Cell,
2002
Simple Intracellular Signaling Induced by an Extracellular
Signaling
A signaling molecule activates its receptor Molecule
→ activation of an intracellular signaling pathway, i.e. a
series of signaling
 Receptors for ligands / Chemical
Messengers
• The cell recognizes a chemical
messenger(CM)when it binds with its specific
receptors on / within cell
• Over 20 families of receptors for CM characterized
• Receptors-not static proteins; number ↑ or ↓
• When a CM is present in excess, its receptors
generally ↓(down-regulation), but when CM is
deficient,there is↑in no.of receptors(up-regulation)
• Angiotensin II is an exception which ↑rather than ↓
the number of its receptors in the adrenal cortex
• Receptor mediated endocytosis is responsible for
down-regulation of receptors from cell membrane;
in some instances, process is called internalization
• Some receptors are recycled after internalization;
others are replaced by de novo synthesis in the cell
• Desensitization is another phenomenon of down-
regulation, where receptors are chemically
modified in ways that make them less responsive
 MECHANISMS BY WHICH CHEMICAL
MESSENGERS ACT
• Cellular receptors are divided into two general
types, cell-surface receptors (CSRs) and
intracellular receptors
• Three general classes of CSRs have been identified:
G-protein-coupled receptors (GPCRs), ion channel
linked receptors, and enzyme-linked receptors
• Intracellular receptors include steroid and thyroid
hormone receptors
• Receptor-ligand (R-L) interaction initiates
downstream signaling in the cell
• Ligands such as ACh bind directly to ion channels in
the cell membrane, changing their conductance
• Thyroid and steroid hormones, and retinoids enter
the cell and act via a family of structurally related
cytoplasmic or nuclear receptors- transcribe DNA
• Cytokines and many other ligands in the ECF bind
to receptors on the surface of cells and trigger the
release of intracellular mediators such as cAMP,
IP3, and DAG that initiate changes in cell function
• R-L coupling brings about the synthesis of
intracellular mediators; thus, ECL ligand is called 1st
messenger and ICL mediators the 2nd messengers
• 2nd messengers affect cell function by altering
enzyme function, triggering exocytosis, etc. and
also by transcription of various genes
• This provides amplification of the primary signal
and distribution of the signal to appropriate targets
within the cell
• Extensive cell signaling pathways also provide
opportunities for feedback and regulation that can
fine-tune the signal for the correct physiological
response by the cell
• Downstream signaling involves phosphorylation /
dephosphorylation of cellular proteins caused by two
group of enzymes;
• Kinases, enzymes that catalyze the phosphorylation of
tyrosine or serine and threonine residues in proteins (or
in some cases, in lipids) &
• Phosphatases, proteins that remove phosphates from
proteins (or lipids)
• Some of the larger receptor families are themselves
kinases, e.g., Tyrosine kinase receptors
• Alternatively, 2nd messenger can lead to phosphorylate
further downstream molecules in the signaling pathway
• More than 500 protein kinases have been described
• Phosphorylation changes the conformation of the
proteins, altering their functions and consequently
the functions of the cell
• The close relationship between phosphorylation
and dephosphorylation of cellular proteins allows
for a temporal control of activation of cell signaling
pathways, sometimes called as a“phosphate timer.”
• The dysregulation of the phosphate timer and
subsequent cellular signaling in a cell can lead to
disease
 Stimulation of Transcription
• Steroids or thyroid hormones-directly bind with nuclear
receptor in the cytoplasm or in the nucleus
• MAP kinase cascade activated, as a result of 2nd
messenger signaling through a variety of R-L
interactions, via phosphorylation of MAP kinases in a
series ; the final member enter the nucleus and
phosphorylate a latent transcription factor (TF)
• 3rd common pathway is the activation of a latent
transcription factor in the cytosol; included are nuclear
factor kappa B (NFκB; activated following tumor
necrosis family receptor binding and others) and signal
transducers of activated transcription (STATs; activated
following cytokine receptor binding).
Ion Channels
 Ion Channel Linked Receptors
• Ion channels, found in all cells, are transmembrane
proteins
• Regulate the flow of ions through plasma membrane
channels
• Natural ligands (NL) are acetylcholine, serotonin, GABA,
and glutamate (synaptic transmitters)
• In some cases, the receptor and ion channel are one
and the same molecule
• Binding of a NL with its receptors→opens the channel
associated with the receptors and transmits its signal
across the plasma membrane by increasing
transmembrane conductance of the relevant ion
• This leads to altering of the electrical potential across
the membrane
• Example is ACh that causes the opening of the
ion channel in the nicotinic receptor (nAChR)
• This allows Na+ to flow down its concentration
gradient into cells, producing a localized excitatory
postsynaptic potential—a depolarization
• Best characterized receptor is nAChR
• It is a pentamer made up of five different
polypeptide subunits (eg, two α chains, one β, one
γ, and one δ chain, all with MW (43,000 to 50,000)
• These polypeptides, each of which crosses the lipid
bilayer four times, form a cylindrical structure that
is 8 nm in diameter
• Binding of ACh with binding sites on the α subunits →
conformational change → transient opening of a
central aqueous channel →Na+ entry frm ECL to cell
• The time elapsed between the binding of the agonist to
a ligand-gated channel and the cellular response can
often be measured in milliseconds
• In other cases, the receptor and an ion channel are
linked via a G protein, 2nd messengers, or other effector
molecules, as in the muscarinic cholinergic receptor on
cells innervated by PNS
• Another possibility is that the ion channel is directly
activated by a cyclic nucleotide, such as cGMP or cAMP,
produced as a consequence of receptor activation-
found predominately in the sensory tissues for sight,
smell, and hearing
 Ligand ( Growth Factors)-Regulated
Tyrosine Kinases Receptors
• GF are polypeptide & proteins- 3 classes
• 1st class-agents that foster the multiplication or
development of various types of cells; insulin-like
growth factor I (IGF-I), activins and inhibins, and
epidermal growth factor (EGF) are examples
• 2nd class-cytokines produced by macrophages and
lymphocytes, as well as other cells, and are
important in regulation of the immune system
• 3rd class-colony stimulating factors(CSF)→ regulate
proliferation and maturation of RBCs& WBCs
• The receptors for the 1st class are polypeptides
consisting of an ECL hormone-binding domain and
an ICL enzyme domain, which may be a protein
tyrosine kinase, a serine kinase,or a guanylyl cyclase
• Signaling begins with binding of ligand to the
receptor’s ECL domain→ conformational change →
dimerization of 2 receptors → activation of intrinsic
tyrosine kinases (TK) in ICL domain → cross
phosphorylation of tyrosine residues (PTR)
• The PTR serve as “docking sites” for additional
signaling molecules or adapter proteins that have a
specific sequence called an SH2 domain
• The SH2-containing adapter proteins may be serine/
threonine protein kinases, phosphatases, or other
proteins that help in the assembly of signaling
complexes that transmit the signal from an
activated receptor to many signaling pathways,
resulting in a cellular response
• One of the pathways activated by phosphorylation
leads, through the small G protein Ras, to MAP
kinases, and eventually to the production of
transcription factors (TF) in the nucleus that alter
gene expression
• Receptors for cytokines and CSF do not have TK
domains in their ICL portions and some have little or no
cytoplasmic tail
• However, they initiate TK activity in the cytoplasm
• A separate protein TK, from the Janus-kinase (JAK)
family, binds non-covalently to the receptor
• R-L binding→Cytokine receptors dimerize →allowing
the bound JAKs to become activated
• This ultimately leads to phosphorylate STAT proteins
• The phosphorylated STATs form homo- and hetero-
dimers and move to the nucleus, where they act as TF
• Four known mammalian JAKs and seven known STATs
 nd
G PROTEIN COUPLED RECEPTORS & 2
Messengers
• GPCRs-largest family of CSRs, +1,000 members
• Indirectly regulate their effector targets-may be ion
channels or plasma membrane-bound effector
enzymes, through another membrane-bound
adapter protein complex called the trimeric GTP-
binding regulatory protein or G protein
• GPCRs ligands include proteins, small peptides,
amino acids, and fatty acid derivatives
• A single ligand can activate several different GPCRs,
e.g., serotonin activates at least 15 different GPCRs
• GPCRs-structural. and functionally similar molecules
• Also called “seven-transmembrane” (7-TM), or
“serpentine” receptors
• So-named because the receptor polypeptide chain
“snakes” across the plasma membrane seven times
• Often the ligand-bound pocket is enclosed by
the transmembrane regions of the receptor
• The ICL domain of the receptor, that couple G-
protein, lies normally in its 3rd cytoplasmic loop
• The R-L coupling results in a conformational change
in the receptor that allows the activation of the
membrane bound G protein
• Activated G protein, then, dissociates from the
receptor and transmits the signal to its effector
enzyme or ion channel
• This element then changes the conc. of the ICL 2nd
messenger, i.e., cAMP, cGMP, IP3 & DAG
• Activation of a single receptor can result in 1, 10, or
more active heterotrimeric G proteins, providing
amplification as well as transduction of the 1st
messenger
• Bound receptors can be inactivated through
phosphorylation of the cytoplasmic side of the
receptor
 G Proteins
• G proteins → diverse group of regulat. proteins
that translate a signal to a biologic effect inside cells
• Become activated after binding GTP
• The G protein exchanges GDP for GTP as a signal
approaches to it
• The GTP–protein complex brings about the
activating effect of the G protein
• The inherent GTPase activity of the protein then
converts GTP to GDP, restoring the G protein to an
inactive resting state
• Divided into 2 groups involved in cell signalling:
• 1. Small G proteins
• Six different families of small G proteins (or small
GTPases ) that are all highly regulated
• GTPase activating proteins (GAPs) tend to inactivate
small G proteins whereas Guanine exchange factors
(GEFs) tend to activate small G proteins
• Some are anchored to membranes due to lipid
modificat. while others free to diffuse in the cytosol
• Examples: The Rab family that regulates the rate of
vesicle traffic; the Rho/Rac family that mediates
interactions between the cytoskeleton and cell
membrane; and the Ras family that regulates growth
• 2. Heterotrimeric G proteins
• Couple CSRs to enzymes that catalyze the formation of
2nd messengers or link receptor directly to ion channels
• Made up of three subunits designated α, β, and γ
• Both the α and the γ subunits have lipid modificat.
• The α subunit is bound to GDP
• As ligand binds with GPCR, the GDP is exchanged for
GTP and the α subunit separates from β and γ
• Both the α subunit and the combined β and γ subunits
independ. act as SMs→activate a variety of effectors
• α subunit intrinsic GTPase activity → GTP to GDP → re-
association of the α with the βγ → ↓effector activation
• Regulators of G protein signaling (RGS) →↑GTPase
activity of the α subunit
Examples of ligands for G-protein coupled receptors
 nd
2 Messengers
• Cyclic AMP or cAMP
• DAG &IP3
• Ca2+
• Cyclic GMP or cGMP
 Cyclic AMP
• cAMP mediates different hormonal responses as:
• - The mobilization of stored energy (burn
carbohydrates in liver or triglycerides in fat cells by
catecholamines)
• - Conservation of water by the kidney (vasopressin)
• - Ca2+ homeostasis (parathyroid hormone), &
• - Increased rate and contractile force of heart
muscle (β-adrenomimetic catecholamines)
• Also regulates the production of adrenal and sex
steroids (in response to corticotropin or FSH)
• Relaxation of smooth muscle, and many other
endocrine and neural processes
• cAMP formed from ATP by the action of the
enzyme adenylyl cyclase (AC) &
• Converted to physiologically inactive 5’AMP by the
action of the enzyme phosphodiesterase (PDE)
• Several cyclic nucleotide PDE are present in the cell
• Milrinone, a selective inhibitor of type 3 PDE
expressed in cardiac muscle cells, has been used as
an adjunctive agent in treating acute heart failure
• Caffeine, theophylline, and other methylxanthines
produce their effects by blocking PDE, thus,
inhibiting cAMP degradation
• cAMP→activation of protein kinase A (or cAMP -
dependent protein kinase) →phosphorylation of
various cellular proteins, ion channels, and TF
• Activity or function of these target proteins alters
leading to a desired cellular response
• In addition, in some cell types, cAMP directly binds
to and affects the activity of ion channels
• Protein kinase A is composed of a cAMP-binding
regulatory (R) dimer and two catalytic (C) chains
• When cAMP binds to the R dimer, active C chains
are released to diffuse through the cytoplasm and
nucleus, where they transfer phosphate from ATP
to appropriate substrate proteins, often enzymes
• The specificity of the regulatory effects of cAMP
resides in the distinct protein substrates of the
kinases that are expressed in different cells
• For example, liver is rich in phosphorylase kinase
and glycogen synthase, enzymes whose reciprocal
regulation by cAMP-dependent phosphorylation
governs carbohydrate storage and release
• In addition, the active catalytic subunit of PKA
moves to the nucleus and phosphorylates the
cAMP-responsive element binding protein (CREB).
This TF, then, binds to DNA and alters transcription
of a number of genes
 Production of cAMP by Adenlyl Cyclase
• AC - a membrane bound protein with 12
transmembrane regions
• Ten isoforms of this enzyme have been described
each having distinct regulatory properties, tailored
to specific cell / tissue need
• Stimulatory G proteins(Gs ) activate, while
inhibitory G proteins (Gi ) inactivate AC
• On binding an appropriate ligand to a stimulatory
receptor, a Gs α subunit activates one of the AC
whereas activation of inhibitory receptor lead to
inhibition of AC via a Gi α subunit
• The receptors are more specific to specific ligands but G
proteins mediate the stimulatory and inhibitory effects
produced by many different ligands
• In addition, cross-talk between the phospholipase C
and the AC systems results in widespread effects of PKA,
as several of the isoforms of AC are stimulated by
calmodulin
• Two bacterial toxins mediate effects on AC through G-
proteins (hence extensively used in G-protein research):
• - cholera toxin catalyzes the transfer of ADP ribose to
an arginine residue in the middle of the α subunit of Gs
inhibiting its GTPase activity, producing prolonged
stimulation of AC
• - Pertussis toxin catalyzes ADP-ribosylation of a
cysteine residue near the carboxyl terminal of the α
subunit of Gi, thus, inhibiting the function of Gi
 nd
IP3 & DAG AS 2 MESSENGERS
• Another effector enzyme is , phospholipase C (PLC),
on the inner leaflet of the plasma membrane
• Ligands bound to GPCR can activate PLC through
the Gq proteins, while those bound to TK receptors
can do this through other cell signaling pathways
• PLC has 8 isoforms; PLC β-activated by G proteins,
while PLCγ forms-activated through TK receptors
• PLC isoforms can catalyze the hydrolysis of the
membrane lipid phosphatidylinositol 4,5-
diphosphate (PIP 2 ) to form IP3 and DAG
• DAG, confined to the membrane, activates one of
several isoforms of protein kinase C (PKC)
• Several tumor-promoting phorbol esters, that mimic
the structure of DAG, activate PKC directly without
receptor activation
• PKC, on activation, phosphorylates specific proteins,
including other enzymes and TF, to produce approp.
physiological effects, such as cell proliferation
• IP3,water-soluble, diffuses to ER to trigger release of
Ca2+ by binding to ligand-gated Ca2+ channels
• The resulting ↑ in cytoplasmic Ca2+ conc. promotes the
binding of Ca2+ to the calcium-binding protein
calmodulin, which regulates activities of other enzymes,
including calcium-dependent protein kinases
• Multiple mechanisms damp or terminate signaling
by this pathway
• IP3 is inactivated by dephosphorylation
• DAG is either phosphorylated to yield phosphatidic
acid, which is then converted back into phospho-
lipids or it is deacylated to yield arachidonic acid
• Ca2+ is actively removed from the cytoplasm by
Ca2+ pumps
 G Protein-Coupled Receptors (GPCR)
• G protein-coupled receptors (GPCR)
– 7 transmembrane domain receptors on the cell membrane that
sense the internal environment
– ligands activate the G protein by causing a conformational change
– this change propagates to a second messenger which detaches
from the GPCR to carry the signal to other effector proteins
• 3 types of GPCR second messengers and functions
– Gq activates phospholipase which results in the formation of
• inositol phosphate (IP3) → ↑ [Ca2+ ]
• diacylglycerol → activation of protein kinase C (PKC)
• examples of receptor types: α1, H1, V1, M1, M3
– Gs activates adenyl cyclase resulting in
• ↑ cAMP → ↑ activity of protein kinase A (PKA)
• examples of receptor types: β1, β2 , D1, H2, V2
– Gi inhibits adenyl cyclase resulting in
• ↓ cAMP → ↓ activity of protein kinase A (PKA)
• examples of receptor types: α2, D2, M2
Receptor GPCR Class Locations and Major Functions

Adrenoceptor: Sympathetic System

α1 q ∙ GI and GU: contraction of sphincters

∙ Eye: contraction of iris radial muscle
(mydriasis)
∙ Vasculature: vasoconstriction
∙ Heart: ↑ contraction force (positive
inotrope) and ↓ heart rate (negative
chronotrope)

α2 i ∙ GI: ↓ motility
∙ Vasculature: vasoconstriction of veins
and arteries in heart BUT vasodilation
of arteries
∙ Presynaptic adrenergic nerve terminals:
↓ sympathetic outflow by inhibiting NE
release
∙ Lipocytes: ↓ decreases lipolysis
∙ Pancreas: ↓ insulin and ↑ glucagon
∙ Platelets: stimulation of platelet
aggregation
β1 S ∙ Heart: positive
chronotrope and
inotrope
∙ Kidney: ↑ renin release
∙ Lipocytes: ↑ lipolysis
β2 S ∙ Vasculature: vasodilation
(specifically skeletal
muscle vasculature)
∙ Lung: bronchodilation
∙ GI and GU: bladder and
uterus relaxation
∙ Heart: positive inotrope
and chronotrope
∙ Eye: ciliary muscle
relaxation
∙ Lipocytes: ↑ lipolysis
∙ Pancreas: ↑ insulin
release
∙ Liver: ↑ gluconeogenesis
M1 q ∙ CNS: excitatory in the
CNS
∙ Glands: ↑ salivary, sweat,
and stomach secretions

M2 i ∙ Heart: negative
chronotrope and ↓
contractility of atria
M3 q ∙ Glands: ↑ salivary, sweat,
stomach glands
∙ GI and GU: ↑ motility, ↑
bladder and uterus
contraction
∙ Lung: bronchoconstriction
∙ Eye: ciliary and iris
circular muscle
contraction
D1 s ∙ Kidney: renal vascular
smooth muscle relaxation

D2 i ∙ Brain: modulates
neurotransmitter release

Other G Protein-Coupled Receptors (Histamine and Vasopressin)

H1 q ∙ Glands; ↑ nasal and
bronchial mucus secretion
∙ Lung: bronchoconstriction
∙ Skin: pruritus (itching), ↑
pain and irritation

H2 s ∙ GI: ↑ gastric acid secretion

V1 q ∙ Vasculature:
vasoconstriction

V2 s ∙ Kidney: antidiuretic, ↑ water

permeability and
reabsorption in the
collecting tubules
 Calcium
• Ca2+ regulates diverse physiological processes as
proliferation, neural signaling, learning, contraction,
secretion, and fertilization
• Cytosolic Ca2+ is about 10,000 times less (10-7 M vs
10-3 M) than in the ECL fluid
• This large gradient is maintained by:
• - Ca2+ transporters in the plasma membrane that
extrude calcium,
• -by Ca2+ pumps in intracellular organelles, and
• -by cytoplasmic and organellar proteins that bind
calcium to buffer its free cytoplasmic concentration
• Many 2 messengers act by ↑ the cytosolic Ca
nd 2+

• IP3 is the major 2 messenger that causes Ca

nd 2+

release from the ER through the direct activation of

a ligand-gated channel, the IP3 receptor
• In many tissues, transient release of Ca2+ from
internal stores into the cytoplasm triggers opening
of a population of Ca2+ channels in the cell
membrane (store-operated Ca2+channels; SOCCs)
• Research has identified the physical relationships
between SOCCs and regulatory interactions of
proteins from the ER that gate these channels
• Cytosolic Ca2+ ↑ by two mechanisms:
• Plasma membrane have voltage-gated Ca2+ ion
channels and allow Ca2+ to come in when it
depolarizes, or these channels may be controlled
by phosphorylation by proteins PKA or PKC
• In addition, ER & other organelle has Ca2+channels
that, when activated, release Ca2+ into the cytosol,
causing an ↑ in cytoplasmic calcium
• ↑ cytoplasmic Ca2+ binds to and activates calcium-
binding proteins (CaBPs)
• CaBPs can have direct effects in cellular physiology,
or can activate other proteins, commonly protein
kinases, to further cell signaling pathways
• Two mechanisms for termination of Ca actions:
2+

• - The IP3 from PLC can be dephosphorylated &

inactivated by cellular phosphatases
• - Cytosolic Ca2+ can be rapidly pumped out to the
ECL space or into an ICL organelle by ATP-driven
Ca2+ pumps in the plasma membrane, ER, SR, and
mitochondrial membranes
• Ca2+ movement into the internal stores is through
the action of the SR or ER Ca2+ATPase , also known
as the SERCA pump
 Calcium Binding Proteins (CaBPs)
• Different CaBPs; troponin, calmodulin, & calbindin
• Troponin-involved in contraction of skeletal muscle
• Calmodulin (Cal) contains 148 amino acid residues and
has four Ca2+ -binding domains
• On binding with Ca2+ , Calmodulin activates five
different calmodulin-dependent kinases (CaMKs)
• One kinase-myosin light-chain kinase (MLCK), phospho-
rylates myosin and cause contraction in smooth muscle
• CaMKI and CaMKII are concerned with synaptic
function, and CaMKIII with protein synthesis
• Another Cal-activated protein is calcineurin, a
phosphatase that inactivates Ca2+ channels by
dephosphorylating them
 Cyclic GMP
• Another cyclic nucleotide of physiologic
importance is cyclic guanosine monophosphate
(cGMP )
• cGMP is important in vision in both rod and cone
cells; in addition, cGMP-regulated ion channels, &
cGMP-dependent kinase → a no. of physiol. effects
• Guanylyl cyclases (GCs) are a family of enzymes
that catalyze the formation of cGMP
• GCs exist in two forms
• One form has an ECL amino terminal domain that is
a receptor, a single transmembrane domain, and a
• Several such GCs have been characterized
• Two are receptors for atrial natriuretic peptide (ANP),
and a third binds an Escherichia coli enterotoxin and
the GI polypeptide guanylin
• The other form of GC is soluble, contains heme, and is
not bound to the membrane
• Several isoforms of the intracellular enzyme, activated
by nitric oxide (NO) and NO-containing compounds
• ↑ cGMP conc. causes relaxation of vascular smooth
muscle by a kinase-mediated mechanism that results in
dephosphorylation of myosin light chains
• The actions are terminated by enzymatic degradation
of the cyclic nucleotide and by dephosphorylation of
kinase substrates
• A no. of useful vasodil. drugs,
such as nitro-glycerin and Na-
nitroprusside used in treating
cardiac ischemia and acute
hypertension, act by
generating or mimicking NO
• Others produce vasodilation by
inhibiting specific phospho-
diesterases, thus, interfering
with the metabolic breakdown
of cGMP
• One such drug is sildenafil,
used in treating erectile
dysfunction and pulmonary
hypertension
Intracellular Receptors&Hormone Signaling
• The ICL receptors can be located in either the
cytosol or the nucleus
• The ligands for these receptors must be lipid soluble
• Result is altered gene expression
• Ligands include the steroids (e.g., estradiol,
testosterone, progesterone, cortisone, and
aldosterone), 1,25-dihydroxy vitamin D3, thyroid
hormone, and retinoids
• On passing plasma membrane of the cell, these
ligands bind to specific receptors that reside either
in the cytoplasm or the nucleus
• The cytoplasmic steroid receptors are usually found
complexed with other proteins that maintain the
receptor in an inactive conformation
• This receptor has 3 domains: N-terminal regulatory
domain (transcriptional activity ), a centrally
located DNA binding domain and a C-terminal
hormone-binding and dimerization domain
• Binding of glucocorticoid to its receptor relieves
associated protein (inhibitory constraint) on the
transcription-stimulating domain of the receptor
• The steroid-receptor complex moves to the nucleus,
where it binds to specific DNA sequences called
hormone response element (HRE) of specific
hormone-responsive gene
• Binding of the hormone-receptor complex to the HRE
can either activate or repress transcription
• While most effects involve increased production of
specific proteins, repressed production of certain
proteins by steroid hormones can also occur
• Newly synthesized proteins and/or enzymes will affect
cellular metabolism with responses attributable to that
particular steroid hormone
• In contrast, the thyroid hormones and retinoic acid bind
to receptors that are already bound to response
elements in the DNA of specific genes
• The lag time required for new protein synthesis require
30 minutes to several hours; so the action of these
hormone is not immediate and persist for hours /days