Module 1A SGD Session 3: Cellular Communication

PHYSIOLOGY (Boron) Dr. Laguardia

5. Discuss the mechanism by which chemical messengers control activity of cells.

5.1 Identify descriptions of the different protein-binding sites (receptors)
5.2 Identify descriptions of characteristics of receptors to include specificity, saturation,
affinity, competition, antagonism and antagonistic activity.
5.3 Identify differences between down-regulation and up-regulation. Identify examples of
each.
5.4 Discuss the signal transduction pathways.
5.4.1 Identify the series of events that takes place in the following:
5.4.1.1 Binding of lipid-soluble messengers to receptors
5.4.1.2 Binding of lipid-insoluble messengers to receptors
5.4.1.3 G protein activation
5.4.1.4 Second messenger activation

Cell-to-cell communication

All cells receive and process information. External signals such as odorants,
metabolites, ions, hormones, growth factors, and neurotransmitters can all serve as chemical
messengers linking neighboring or distant cells.

Most chemical messengers interact with specific cell-surface receptors and trigger a
cascade of secondary events, including the activation of intracellular second-messenger
systems that mediate the cell's response to that stimulus. However, hydrophobic messengers,
such as steroid hormones and some vitamins, can diffuse across the plasma membrane and
interact with cytosolic or nuclear receptors.

Mechanisms of Cellular Communication

Cells secrete chemical signals that can induce a physiological response :

 by entering the circulation and acting on distant tissues (endocrine),

 by acting on a neighboring cell in the same tissue (paracrine)
 by stimulating the same cell that released the chemical (autocrine)
 by physical contact between one cell and another, or between a cell the matrix
secreted by another cell, can transmit a signal (juxtacrine); their diffusion must
be limited. This restriction can be accomplished by rapid endocytosis of the
chemical signal by neighboring cells, its destruction by extracellular enzymes, or
its immobilization by the extracellular matrix
o Gap Junctions
o Adhering and Tight Junctions

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Receptor

For a molecule to act as a signal, it must bind to a receptor. Most receptors are proteins
(or some cases lipoproteins and glycoproteins) on the cell surface or within the cell that
specifically bind a signaling molecule (the ligand) and induce a cellular response by interacting
with an effector

In some cases, the receptor is itself the effector, as in ligand-gated ion channels that
alter transmembrane ion conductance in response to an extracellular signal. In most cases,
however, interaction of the ligand with its receptor results in association of the receptor with one
or more intracellular effector molecules that in turn initiate the cellular response. Effectors
include enzymes, channels, transport proteins, contractile elements, and transcription factors.

Receptors can be divided into five categories on the basis of their mechanisms of signal
transduction

1. Ligand-gated ion channels. Integral membrane proteins, these hybrid receptors/channels

are involved in signaling between electrically excitable cells Ligand-gated ion channels
transduce a chemical signal into an electrical signal.

2. G protein–coupled receptors. These integral plasma-membrane proteins work indirectly—

through multiple intermediaries—to activate or inactivate downstream effectors, such as
membrane-associated enzymes or channels. This group of receptors is named for the initial
intermediary, which is a heterotrimeric GTP-binding complex called a G protein.

3. Catalytic receptors. When activated by a ligand, these integral plasma-membrane proteins

are either enzymes themselves or part of an enzymatic complex. In many cases, these
receptors are either kinases that add phosphate groups to their substrates or phosphatases
that remove substrate phosphate groups.

4. Nuclear receptors. These proteins, located in the cytosol or nucleus, are ligand-activated
transcription factors. These receptors link extracellular signals to gene transcription.

5. Receptors that undergo cleavage. In response to ligand binding, some transmembrane

proteins undergo regulated intramembranous proteolysis,which liberates one or more
fragments of their cytosolic domain that signal a cellular response by entering the nucleus to
modulate gene expression

Receptor Characteristics

1. Specificity- only one type or limited number of structurally related types of chemical
messenger
2. Saturation- degree to which receptors are occupied by chemical messengers
3. Affinity- strength with which a chemical messenger binds to the receptor
4. Competition- ability of different molecules to compete with a ligand for binding to its
receptor

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5. Antagonism- occurs when a molecule competes with a ligand for binding to its receptor
but does not activate signaling
6. Agonistic activity- occurs when a molecule or chemical messenger binds to a receptor
and trigger cell’s response (amplifies)

Hormone Receptor Regulation

The number of receptors a cell has and the affinity of the receptors for their specific messengers
can be increased or decreased.

Down regulation- When a high concentration of messengers in the extracellular fluid is

maintained receptors are diminished (endocytose)
Up regulation- When there is low extracellular concentration of messengers, the target cells
increases the number of receptors (exocytose)

CHEMICAL MESSENGERS

1. Lipid-soluble messengers
 Generally act on cells by binding to intracellular receptor protein.
 Steroids hormones, thyroid hormones, vitamin D
2. Lipid-insoluble messengers
 Exert their actions on cells by binding to extracellular portion of the receptor
proteins embedded in plasma membrane
 Receptors that are ligand-gated ion channels
 Receptors that function as enzyme
 Receptors that interact with Janus kinase

Soluble chemical signals interact with via binding to surface or intracellular receptors
Four types of chemicals can serve as extracellular signaling molecules: NOT IMPORTANT

1. Amines, such as epinephrine

2. Peptides and proteins, such as angiotensin II and insulin
3. Steroids, including aldosterone, estrogens, and retinoic acid
4. Other small molecules, such as amino acids, nucleotides, ions (e.g., Ca2+), and gases
(e.g., nitric oxide)

SIGNAL TRANSDUCTION PATHWAYS

Signaling events initiated by membrane-associated receptors can generally be divided
into six steps

Step 1: Recognition of the signal by its receptor.

Step 2: Transduction of the extracellular message into an intracellular signal or second
messenger.
Step 3: Transmission of the second messenger's signal to the appropriate effector.
Step 4: Modulation of the effector. These effectors represent a diverse array of
molecules, such as enzymes, ion channels, cytoskeletal components, and
transcription factors

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Step 5: Response of the cell to the initial stimulus. This collection of actions represents
the summation and integration of input from multiple signaling pathways
Step 6: Termination of the response by feedback mechanisms at any or all levels of the
signaling pathway.

G PROTEIN COUPLED RECEPTOR

G proteins
 They consist of a single polypeptide chain with seven membrane- spanning α-helical
segments, an extracellular N terminus that is glycosylated, a large cytoplasmic loop that
is composed mainly of hydrophilic amino acids between helices 5 and 6, and a
hydrophilic domain at the cytoplasmic C terminus.
 5-6 cytoplasmic loop- major site of interaction with intracellular G-protein
Some cases involves, 3-4 cytoplasmic loops and C terminus
 They hydrolyze GTP and switch between active GTP-bound state
and inactive GDP-bound state

G proteins are heterodimers composed of three sub units: α (16 diff. Types), β (5), and γ(11).
 α subunit - binds to GTP and hydrolyzes and interacts with effector proteins
 α and γ anchor the protein to the membrane
 βγ complex also interacts with effector molecules
 Adenyl cyclase : Gs stimulates adenyl cyclase ( Vibrio cholerae activates this)
Gi inhibits adenyl cyclase (Bordetella pertussis inactivates this)

G protein activation cycle (Heterotrimeric enzymatic cycle)

1. G protein in inactive state with αβγ complex with GDP at α subunit

2. Ligand binds to GPCR (G-protein coupled receptor) and activates it
3. G protein interacts with receptor and changes conformation with the release of GDP and
simultaneous binding of GTP
4. GTP binding stimulates dissociation of the complex from the receptor and disassembly
of α and βγ complex
5. The free GTP bound α subunit interacts with effectors (e.i adenyl cyclase) .βγ complex
also interacts with effector molecules (ion channels and other effectors)
6. RGS (regulation for G protein signaling) binds to α subunit, stimulates hydrolysis of GTP
to GDP which inactivates α subunit and promotes reassembly of the trimer.

α subunit coupled to downstream effectors:

 G protein activates(Gs)/inhibits(Gi) adenyl cyclase
 G protein activates enzymes that breakdown cyclic nucleotides: Photoransduction:
Transducin (G-protein) activates cGMP phosphodiesterase which catalyzes breakdown
of cGMP to GMP
 G protein also couples to phospholipases A2, C, and D which are grouped based on the
phospholipid site they cleave
 Some G proteins interact with ion channels
 G proteins serve additional functions in membrane trafficking

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βγ complex downstream effectors (NI)

 Musccarine , an alkaloid in certain poisonous mushrooms stimulates release of Ach from

vagus nerve which reduces rate and strength of heart contraction
ACh binds to muscarinic M2 AChR(in atria) activating G protein and generating active
Gαi and βγ complex. βγ complex interacts with K + channels increasing their permeability
keeping the membrane potential negative, making cells more resistant to excitation.
 βγ complexes bind to protein kinase called the β adrenergic receptor kinase (βARK)
which translocates to the plasma membrane then phosphorylates the ligand-receptor
complex (not the unbound receptor) resulting in the recruitment of β- arrestin to the
GPCR, which mediates disassociation of the receptor-ligand complex and thus
decreases the activity of the β adrenergic receptors. This action is an example of
receptor desensitization. These receptors eventually undergo endocytosis to reduce
the number of receptors on the cell surface, an important step in resensitization of the
receptor system.

Small GTP binding proteins (NI)

 Divided into five groups: Ras, Rho, Rab, Arf, Ran

 Ras (N, Ha, Ki) relay signals from plasma membrane to nucleus through kinase cascade
thereby regulating gene expression. Mutated gene encoding Ras proteins are
constitutively active and the mutated genes are called oncogenes because product
results to malignant transformation of a cell contributing to development of cancer
 GTP binding proteins switching inactive GDP-bound form and active GTP-bound form
includes GTPase activating proteins (GAPs) increasing rate of hydrolysis. Counteracting
its activity is done by Guanine nucleotide exchange proteins (GEFs), cAMP directly
activates GEFs.

G-PROTEIN SECOND MESSENGERS: cyclic nucleotides (cAMP & cGMP)

 Activation of Gs-coupled receptors results in the stimulation of adenylyl cyclase, which

can cause [cAMP]i to rise 5-fold in ~5 seconds This sudden rise is counteracted by
cAMP breakdown to AMP by cAMP phosphodiesterase.
 cAMP exerts many of its effects through cAMP-dependent protein kinase A (PKA).
This enzyme catalyzes transfer of the terminal phosphate of ATP to specific serine or
threonine residues on substrate proteins. PKA phosphorylation sites are present in a
multitude of intracellular proteins, including ion channels, receptors, metabolic enzymes,
and signaling pathway proteins.

G-PROTEIN SECOND MESSENGERS: PRODDUCTS OF PHOSPHOINOSITIDE BREAKDOWN

 The phosphoinositidols (not abundant) of membrane can be phosphorylated to

phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 or PIP2) and phosphatidylinositol
3,4,5 trisphosphate (PI(3,4,5)P3 or PIP3

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 Certain membrane-associated receptors act though G proteins (e.g., Gq) that stimulate
phospholipase C (PLC) to cleave PIP2 into inositol 1,4,5 trisphosphate (or IP3) and
diacylglycerol (DAG)
 PLCs are classified into 3 families: (β, γ, δ) PLCβ is typically activated downstream of
certain G proteins (e.g., Gq), whereas PLCγ contains an SH2 domain and is activated
downstream of certain tyrosine kinases. PLCβ results in increase in cytosolic IP3 levels
as well as an early peak in DAG levels.
 Phosphatidylcholines (PCs) (abundant) are also a source of DAG. PLC can directly
convert PC to phosphocholine and DAG. Phospholipase D (PLD), by cleaving the
phosphoester bond on the other side of the phosphate, can convert PC to choline and
phosphatidic acid This PA can then be converted to DAG via PA-phosphohydrolase.
Production of DAG rom PC produces the slow wave of increasing cytosolic DAG.

IP3

 IP3 travels through the cytosol and binds to the IP3 receptor, a ligand-gated Ca2+
channel located in the membrane of the endoplasmic .The result is a release of Ca2+
from intracellular stores and a rise in [Ca2+]i .
 Structurally related to ITPRs are the Ca2+-release channels known as ryanodine
receptors (RYRs)in sarcoplasmic reticulum . Cytosolic Ca2+ activates RYRs thus
elevating [Ca2+]i by a process known as calcium-induced Ca2+ release (CICR).
Moreover, cyclic ADP ribose (cADPR), the product of ADP-ribosylcyclases, increases
the sensitivity of RYR to cytosolic Ca2+, thereby amplifying CICR.
 Increases in [Ca2+]i activate an ATP-fueled Ca pump (SERCA;) that begins pumping
Ca2+ back into the ER. Ca pump and Na-Ca exchanger at the plasma membrane
extrude excess Ca2+ from the cell. These processes are much slower than Ca2+
release, so [Ca2+]i remains high until IP3 is dephosphorylated, terminating Ca2+
release.

Calcium activates calmodulin-dependent protein kinases

 CaM is a high-affinity cytoplasmic Ca2+-binding protein of 148 amino acids. Each

molecule of CaM cooperatively binds four calcium ions inducing a major conformational
change in CaM that allows it to bind to other proteins. CaM does not have enzymatic
activity, it forms a complex with a number of enzymes. For example, binding of the
Ca2+- CaM complex activates the enzyme that degrades cAMP, cAMP
phosphodiesterase.
 Many of the Ca2+-CaM complex binds to CaM kinases (CaMKs). These kinases
phosphorylate specific serine and threonine residues of a variety of proteins. An
important CaMK in smooth-muscle cells is myosin light-chain kinase (MLCK). Another
CaMK is glycogen phosphorylase kinase (PK), which plays a role in glycogen
degradation.

DAGs and Ca2+ activate protein kinase C

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 The most important function of DAG is to activate protein kinase C (PKC), an

intracellular serine/threonine kinase.
 PKC can also directly or indirectly modulate transcription factors and thereby enhance
the transcription of specific genes

G-PROTEIN SECOND MESSENGERS: ARACHIDONIC ACID METABOLITES

Phospholipase A2 is the primary enzyme responsible for releasing AA

 Binding of an extracellular agonist to a membrane receptor can activate a G protein that

belongs to the Gi/Go family.
 The G-protein βγ dimer may stimulate PLA2 either directly or via mitogen-activated
protein kinases (MAPKs) which phosphorylates PLA2 at a serine residue resulting to
rapid hydrolyis of phospholipid to AA
 AA indirect release: First a ligand may bind to a receptor coupled to PLC, which would
lead to the release of DAG, DAG lipase can cleave DAG to yield AA and a
monoacylglycerol (MAG)
 Second, any agonist that raises [Ca2+]i can promote AA formation because Ca2+ can
stimulate some cytosolic forms of PLA
 Third, any signal-transduction pathway that activates MAPK can also enhance AA
release because MAPK phosphorylates PLA

Cyclooxygenases

Cyclooxygenases catalyze the stepwise conversion of AA into the intermediates

prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2). PGH2 is the precursor of the other
prostaglandins, the prostacyclins and the thromboxanes

The metabolism of PGH2 to generate selected prostanoid derivatives is cell specific.

 Platelets convert PGH2 to thromboxane A 2 (TXA2), aggregate platelets, bring about

the platelet release reaction, and constrict small blood vessels.
 Endothelial cells convert PGH2 to prostacyclin I2 (PGI2), which inhibits platelet
aggregation and dilates blood vessels.
 Many cell types convert PGH2 to prostaglandins. Acting locally in a paracrine or
autocrine fashion, prostaglandins are involved in such processes as platelet
aggregation, airway constriction, renin release, and inflammation. 
 Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, acetaminophen,
ibuprofen, indomethacin, and naproxen directly target cyclooxygenase.

The diverse cellular responses to prostanoids are mediated by a family of G protein

coupled prostanoid receptors. These prostanoid receptors signal via Gq, Gi, or Gs, depending
on cell type. These in turn regulate intracellular adenylyl cyclase and phospholipases

Lipoxygenase

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Many lipoxygenase metabolites of AA have a role in allergic and inflammatory diseases. 

LTB4 is produced by inflammatory cells such as neutrophils and macrophages. The cysteinyl
leukotrienes including LTC4 and LTE4 are synthesized by mast cells, basophils, and
eosinophils, cells that are commonly associated with allergic inflammatory responses such as
asthma and urticaria.

Epoxygenase

 The HETEs and EETs (epoxygenase products) tend to enhance Ca2+ release from
intracellular stores and to enhance cell proliferation.
 HETEs enhance Ca2+ release from intracellular stores and promote cell proliferation. In
blood vessels, HETEs can be potent vasoconstrictors
 EETs enhance the release of Ca2+ from intracellular stores, increase Na-H exchange,
and stimulate cell proliferation. In blood vessels, EETsprimarily induce vasodilation and
angiogenesis, although they have vasoconstrictive properties in the smaller pulmonary
blood vessels

CATALYTIC RECEPTORS

1. Receptor guanylyl cyclases catalyze the generation of cGMP from GTP.

2. Receptor serine/threonine kinases phosphorylate serine or threonine residues on
cellular proteins
3. Receptor tyrosine kinases (RTKs) phosphorylate tyrosine residues on themselves
and other proteins.
4. Tyrosine kinase–associated receptors interact with cytosolic (i.e., not membrane-
bound) tyrosine kinases.
5. Receptor tyrosine phosphatases cleave phosphate groups from tyrosine groups of
cellular proteins.

Receptor (Membrane-Bound) Guanylyl Cyclase

 The receptor guanylyl cyclase transduces the activity of atrial natriuretic peptide,
whereas a soluble guanylyl cyclase transduces the activity of nitric oxide
 These ligands are a family of related small proteins (~28 amino acids) including atrial
natriuretic peptide (ANP), B-type or brain natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP).
 Blood vessel dilation and Na secretion = lowering BP
 Binding of ligand induces conformational change in receptor and causes dimerization
and activation. It causes conversion of GTP to cGMP which in turn activates cGMP
kinase.

Soluble Guanylyl Cyclase

 The receptor for NO is soluble cyclase. NO plays a vital role in control of blood flow and
pressure
 Angina pectoris

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Receptor serine/threonine kinase

The receptors for TGF-B are receptor serine/threonine kinase. Receptors type I and type II are
required for ligand binding and catalytic activity. Receptor II first binds the ligand following the
formation of ternary complex of receptor I,II and ligand. Recruitment of Receptor I results in
phosphorylation of type I receptor at ser/thr residues, which in turns activates activity of type I
receptor and propagate signal to downstream effectors.

Receptor tyrosine kinase

All RTKs discovered to date phosphorylate themselves in addition to other cellular proteins.
Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial
growth factor (VEGF), insulin and insulin-like growth factor type 1 (IGF-1), fibroblast growth
factor (FGF), and nerve growth factor (NGF) can all bind to receptors that possess intrinsic
tyrosine kinase activity.

Binding of a ligand induces conformational change that facilitates the formation of dimers.
Dimerization (except insulin and IGF-1 receptors) allows phosphorylation of two catalytic
domains of receptors and thereby activates the receptor complex. The activated receptor
catalyzes the addition of phosphate to tyrosine residue on specific cytoplasmic residues. The
resulting phosphotyrosine (pY) motifs serve as high-affinity binding sites for the recruitment of
proteins that contain either an SH2 domain or PTB (phosphotyrosine-binding) domain

The MAPK Pathway

A common pathway by which activated RTKs transduce their signal to cytosol and even to the
nucleus is a cascade of events that increase the activity of the small GTP-binding protein Ras.
This Ras dependent signaling pathway involves the following steps:

 Step 1: A ligand binds to the extracellular domain of a specific RTK, thus causing
receptor dimerization.
 Step 2: The now-activated RTK phosphorylates itself on tyrosine residues of the
cytoplasmic domain (autophosphorylation).
 Step 3: GRB2, an SH2-containing protein, recognizes pY residues on the activated
receptor.
 Step 4: Because GRB2 constitutively associates with the guanine nucleotide exchange
factor SOS (son of sevenless), via an SH3- proline interaction, the recruitment of GRB2
automatically results in the recruitment of SOS as well.
 Step 5: SOS activates the small G protein Ras by catalyzing the replacement of GDP
with GTP.
 Step 6: The activated GTP-Ras complex activates other proteins by physically recruiting
them to the plasma membrane. In particular, active GTP-Ras interacts with the N-
terminal portion of the cytosolic serine/threonine kinase Raf-1 (also known as MAP
kinase kinase kinase or MAPKKK or MAP3K), which is the first in a series of
sequentially activated protein kinases that ultimately transmits the activation signal.

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 Step 7: Raf-1 phosphorylates and activates a protein kinase called MEK (also known as
MAP kinase kinase or MAPKK). MEK is a multifunctional protein kinase that
phosphorylates substrates on both tyrosine and serine/threonine residues.
 Step 8: MEK phosphorylates MAPKs, cytosolic serine/threonine kinases also called
extracellular signal–regulated kinases (ERK1, ERK2). Activation of MAPK requires dual
phosphorylation on neighboring serine and tyrosine residues. Raf, MEK, and MAPK
typically assemble on a scaffolding protein at the inner side of the cell membrane to
facilitate interaction/phosphorylation during the activation process.
 Step 9: MAPK is an important effector molecule in Ras-dependent signaling to the
cytoskeleton. MAPK phosphorylates multiple proteins involved in actin cytoskeletal
assembly and cell-matrix interactions; this phosphorylation leads to Ras-dependent
changes in cell morphology and cell migration.
 Step 10: Once activated, MAPK disassociates from the scaffold and translocates
primarily to the nucleus, where it phosphorylates a number of nuclear proteins that are
transcription factors. The result is either enhancement or repression of the DNA binding
and transcriptional activity of these nuclear proteins. 

Tyrosine kinase associated receptors

Receptors for cytokines and growth factors that regulate cell proliferation and differentiation
associate with nonreceptor tyrosine kinases Receptors in this class include those for several
cytokines, including IL-2, IL-3, IL-4, IL-5, IL-6, leukemia inhibitory factor (LIF), granulocyte-
macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). The family also
includes receptors for growth hormone (GH), prolactin (PRL), leptin, ciliary neurotrophin factor
(CNTF), oncostatin M, and IFN-α, IFN-β, and IFN-γ.

The tyrosine kinase–associated receptors typically comprise multiple subunits that form
homodimers (αα), heterodimers (αβ), or heterotrimers (αβγ). None of the cytoplasmic portions of
the receptor subunits contains kinase domains or other sequences with recognized catalytic
function. Instead, tyrosine kinases of the Src family and Janus family (JAK or Janus kinases)
associate noncovalently with the cytoplasmic domains of these receptors. Thus, these are
receptor-associated tyrosine kinases. Ligand binding to these receptors results in receptor
dimerization and activation of the associated tyrosine kinase. The activated kinase then
phosphorylates tyrosines on both itself and the receptor. A key difference is that for the tyrosine
kinase–associated receptors, the receptors and kinases are encoded by separate genes and
the proteins are only loosely associated with one another.

Receptor tyrosine phosphatases

Tyrosine residues that are phosphorylated by the tyrosine kinases are

dephosphorylated by PTPs, which can be either cytosolic or membrane spanning (i.e., the
receptor tyrosine phosphatases). Because the tyrosine phosphatases are highly active, pY
groups tend to have a short half-life and are relatively few in number in unstimulated cells.
The CD45 protein, found at the cell surface of T and B lymphocytes, is an example of a
receptor tyrosine phosphatase.

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NUCLEAR RECEPTORS

A number of important signaling molecules produce their effects not by binding to receptors on
the cell membrane but by binding to nuclear receptors (NRs)—also called intracellular
receptors—that can act as transcription regulators. This family includes receptors for steroid
hormones, prostaglandins, vitamin D, thyroid hormones, and retinoic acid. Thyroid hormones,
which are charged amino-acid derivatives, may cross the cell membrane either by diffusion or
by carrier-mediated transport. Once inside the cell, these substances bind to intracellular
receptors. The ligand-bound receptors are activated transcription factors that regulate the
expression of target genes by binding to specific DNA sequences. In addition, steroid hormones
can have nongenomic effects.

The intracellular localization of the different unoccupied receptors varies. The glucocorticoid
(GR) and mineralocorticoid (MR) receptors are mainly cytoplasmic, the estrogen (ER) and
progesterone (PR) receptors are primarily nuclear, and the thyroid hormone (TR) and retinoic
acid (RAR) receptors are bound to DNA in the nucleus. Cytoplasmic receptors are frequently
complexed to chaperone (or “heat shock”) proteins. Hormone binding induces a conformational
change in these receptors that causes dissociation from the cytoplasmic chaperone and
unmasks a nuclear transport signal that allows the hormone-receptor complex to translocate
into the nucleus. Nuclear receptors contain five to six functionally distinct domains that are
differentially conserved among the various members of the family. The N-terminal A/B region
differs most widely among receptors and contains the first of two transactivation domains.
Transactivation is the process by which a ligand-induced conformational change of the
receptor results in a change in conformation of the DNA and thus initiates transcription. The C
region, the most highly conserved among receptor types, contains the DNA-binding domain and
is also involved in dimerization. The D, or hinge, region contains the “nuclear localization
signal” and may also contain transactivation sequences. The E domain is responsible for
hormone binding. Finally, like theA/B region, the E region contains a transactivation domain.

Activated nuclear receptors bind to sequence elements in the regulatory region of responsive
genes and either activate or repress DNA transcription One of the remarkable features of
nuclear receptors is that they bind very specifically to short DNA sequences—called hormone
response elements—in the regulatory region of responsive genes.

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