G Protein Coupled Receptors

G PROTEIN COUPLED
RECEPTORS
STRUCTURAL AND FUNCTIONAL FAMILIES OF
PHYSIOLOGICAL RECEPTORS.
 Receptors for physiological regulatory molecules can be assigned to
functional families whose members share similar molecular
structures and biochemical mechanisms with common features.
 The basic structure of their ligand-binding domains, effectors

domains, and how agonist binding influences the regulatory activity
of the receptor is well understood for each of these signal
transduction systems.
 The relatively small number of biochemical mechanisms and

structural formats used for cellular signaling fundamental to the
ways in which target cells integrate signals from multiple receptors
to produce additive, sequential, synergistic, or mutually inhibitory
responses.
G PROTEIN-COUPLED RECEPTORS
(GPCRS)
G protein coupled receptors are also called as the seven trans
membrane receptors.
GPCRs span the plasma membrane as bundle of seven α-helices.

Receptors and G Proteins:
 Humans express over 800 GPCR and half of these

are dedicated to sensory perception (smell, taste and
vision).
 The remaining receptors regulate an impressive
number of physiological functions including;
 nerve activity,
 tension of smooth muscle,
 metabolism,
 rate and force of cardiac contraction
 the secretion of most glands in the body

LIGANDS THAT BIND TO THESE
RECEPTORS
 Neurotransmitters (eg.Ach)
 Biogenic amines (eg. NE)
 Eicosanoids and other lipid signaling molecule.
 Peptide hormones
 Opioids
 Amino acids (eg. GABA)
 Other miscellaneous peptide and protein ligands.

 GPCRs are important regulators of nerve activity in the
CNS and are the receptors for the neurotransmitters of
the peripheral autonomic nervous system.
 For example,
 Ach released by the parasympathetic nervous system
regulates the function of glands and smooth muscle
through its action on muscarinic receptors.
 NE released by sympathetic nervous system interacts

with α and β adrenergic receptors to regulate cardiac
function and the tone of vascular smooth muscle.
 Because of their number and physiological importance,

GPCRs are the targets for many drugs; perhaps half of
all non-antibiotic prescription act at these receptors.
RECEPTOR SUBTYPE
 There are multiple receptor subtypes within families of receptors.
 Distinct but related receptors may display distinctive patterns of

selectivity among agonist or antagonist ligands. When selective
ligands are not known, the receptors are more commonly referred to
as isoforms rather than as subtypes.
 The distinction between classes and subtypes of receptors, however,

is often arbitrary or historical. The α1, α2, and β adrenergic receptors
differ from each other both in ligand selectivity and in coupling to G
proteins (Gq, Gi, Gs, respectively), yet α and β are considered receptor
classes and α1 and α2 are considered subtypes.
 The α1A, α1B, and α1C receptor isoforms differ little in their
biochemical properties, although their tissue distributions are
distinct. The β1, β2, and β3 adrenergic receptor subtypes exhibit
differences in both tissue distribution regulation by phosphorylation
by G-protein receptor kinases (GRKs) and PKA.
 Pharmacological differences among receptor sub-types are exploited
therapeutically through the development and use of receptor-
selective drugs. Such drug may be used to elicit different responses
from a single tissue when receptor subtypes initiate different
intracellular signals, or they may serve to differentially modulate
different cells or tissues that express one or another receptor
subtype.
 For example, β2 adrenergic agonists such as terbutaline are used for

bronchodilation in the treatment of asthma in the hope of minimizing
cardiac side effects caused by stimulation of the β1 adrenergic
receptor. Conversely, the use of β1-selective antagonists minimizes
the chance of bronchoconstriction in patients being treated for
hypertension or angina.
 Increasing the selectivity of a drug among tissues or among

responses elicited from a single tissue may determine whether the
drug's therapeutics benefits outweigh its unwanted effects.
DIMERIZATION OF GPCR
 GPCRs undergo both homo- and heterodimerization

and possibly oligomerization.
 Heterodimerization can result in receptor units with

altered pharmacology compared with either individual
receptor.
 Eg. opioid receptors can exist as homodimers of or

receptors, or as heterodimers with distinctly different
pharmacodynamic properties than either homodimer.
DIMERIZATION OF GPCR
 Dimerization of receptors may regulate the affinity and
specificity of the complex for G proteins, and regulate
the sensitivity of the receptor to phosphorylation by
receptor kinases and the binding of arrestin, events
important in termination of the action of agonists and
removal of receptors from the cell.
 Dimerization also may permit binding of receptors to

other regulatory proteins such as transcription factors.
 Dimerization of single membrane spanning receptors is

central to their activation.
G- PROTEINS
 GPCRs couple to a family of heterotrimeric GTP-
binding regulatory proteins termed G proteins.
 G proteins are signal transducers that convey the

information that agonist is bound to the receptor from
the receptor to one or more effector proteins.
 G–protein-regulated effectors include enzymes such as

adenylyl cyclase, phospholipase C, cyclic GMP
phosphodiesterase (PDE6), and membrane ion
channels selective for Ca2+ and K+ .
STRUCTURE OF G-PROTEINS
 G Protein is a hetrotrimer.
 The G protein heterotrimer is composed of
1. Guanine nucleotide-binding
α subunit(which confers
specific recognition to both
receptors and effectors), and
2. An associated dimer of β and γ subunits that
helps confer membrane localization of the G protein
heterotrimer.
 In the basal state of the receptor-heterotrimer
complex, the α subunit contains bound GDP and
the –α GDP: βγ complex is bound to the
unliganded receptor
G PROTEIN- SUBUNITS
 The G protein family is comprised of
 23 α subunits (which are the products of 17
genes)
 7 β subunits, and
 12 γ subunits.
 The α subunits fall into four families (Gs, Gi, Gq,

and G12/13) which are responsible for coupling
GPCRs to relatively distinct effectors.
TARGETS FOR G-PROTEINS
The main targets for G-proteins, through which GPCRs
control different aspects of cell function.
 adenylyl cyclase, the enzyme responsible for cAMP
formation. Gs, α subunit uniformly activates adenylyl
cyclase; Gi α subunit can inhibit certain isoform of adenylyl
cyclase
 phospholipase C, the enzyme responsible for inositol
phosphate and diacylglycerol (DAG) formation. Gq α subunit
activates all form of PLC
 ion channels, particularly calcium and potassium channels
are some of the effectors of free β¥ dimer.
 Rho A/Rho kinase, a system that controls the activity of
many signaling pathways controlling cell growth and
proliferation, smooth muscle contraction, etc.
ACTIVATION OF GPCR
 When an agonist binds to a GPCR, there is a
conformational change in the receptor that is
transmitted from the ligand-binding pocket to the
second and third intracellular loops of the receptor
which couple to the G protein heterotrimer.
 This conformational change causes the α subunit to

exchange its bound GDP for GTP.
 Binding of GTP activates the α subunit and causes it to
release both the βγ dimer and the receptor, and active
signaling molecules, both the GTP-bound α subunit
and the βγ heterodimer become and active
signaling molecules.
 The interaction of the agonist-bound GPCR with the G

protein is transient; following activation of one G
protein, the receptor is freed to interact with other G
proteins.
 Depending on the nature of the subunit, the active,
GTP-bound form binds to and regulates effectors
such as adenylyl cyclase (via Gs ) or phospholipase C
(via Gq ).
 The subunit can regulate many effectors including

ion channels and enzymes such as PI3-K. The G
protein remains active until the GTP bound to the
subunit is hydrolyzed to GDP.
 The α subunit has a slow intrinsic rate of GTP

hydrolysis that is modulated by a family of proteins
termed regulators of G protein signaling (RGSs).
 The RGS proteins greatly accelerate the hydrolysis of
GTP and are potentially attractive drug targets.
 Once the GDP bound to the α subunit is hydrolyzed to

GDP, the βγ subunit and receptor recombine to form
the inactive receptor-G protein heterotrimer basal
complex that can be reactivated by another ligand-
binding event.
REFERENCE
 Goodman and Gilman Textbook of Pharmacology.
 Internet sources.
THANK YOU

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G PROTEIN COUPLED

 The basic structure of their ligand-binding domains, effectors

 The relatively small number of biochemical mechanisms and

GPCRs span the plasma membrane as bundle of seven α-helices.

 Humans express over 800 GPCR and half of these

 tension of smooth muscle,

 rate and force of cardiac contraction

 the secretion of most glands in the body

 Biogenic amines (eg. NE)

 Eicosanoids and other lipid signaling molecule.

 Amino acids (eg. GABA)

 Other miscellaneous peptide and protein ligands.

 NE released by sympathetic nervous system interacts

 Because of their number and physiological importance,

 Distinct but related receptors may display distinctive patterns of

 The distinction between classes and subtypes of receptors, however,

 For example, β2 adrenergic agonists such as terbutaline are used for

 Increasing the selectivity of a drug among tissues or among

 GPCRs undergo both homo- and heterodimerization

 Heterodimerization can result in receptor units with

 Eg. opioid receptors can exist as homodimers of or

 Dimerization also may permit binding of receptors to

 Dimerization of single membrane spanning receptors is

 G proteins are signal transducers that convey the

 G–protein-regulated effectors include enzymes such as

 The G protein heterotrimer is composed of

 The α subunits fall into four families (Gs, Gi, Gq,

 This conformational change causes the α subunit to

 The interaction of the agonist-bound GPCR with the G

 The subunit can regulate many effectors including

 The α subunit has a slow intrinsic rate of GTP

 Once the GDP bound to the α subunit is hydrolyzed to

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