Review on G protein coupled receptors
A Satish Chandra, M Rama Krishna, Prof. G Nagarjuna Reddy, R Ramesh
Department of Pharmacology, KLR Pharmacy College,
Palvoncha
ABSTRACT
G
protein-coupled receptors (GPCRs) are involved in the control of every aspect of our
behavior and physiology. This is the largest class of receptors, with several hundred GPCRs
identified thus far. Examples are receptors for hormones such as calcitonin and luteinizing
hormone or neurotransmitters such as serotonin and dopamine. G protein-coupled receptors can
be involved in pathological processes as well and are linked to numerous diseases, including
cardiovascular and mental disorders, retinal degeneration, cancer, and AIDS. More than half of
all drugs target GPCRs and either activates Orin activate them. Binding of specific ligands, such
as hormones, neurotransmitters, chemokines, lipids, and glycol proteins ,activates GPCRs by
inducing or stabilizing a new conformation in the receptor(1, 2). Activated receptors (R*) can
then activate hetero trimetric G proteins (composed of a.GDP, b, and g subunits) on the inner
surface of the cell membrane (3–5).GPCRs have a common body plan with seven trans
membrane helices. The intracellular loops that connect these helices form the G protein-binding
domain reviewed by. 5–7. How do GPCRs activate G proteins and cause such specific responses
in cells? What are the triggering changes in GPCRs on agonist binding? How do they fold, and
what causes misfoldingin so many genetic diseases? All of these unanswered questions in the
field depend on detailed structural information. Recently, the first high-resolution structure of a
GPCR, rhodopsin, the visual light receptor, was solved by the groups of Palczewski, Okada,
Stenkamp, and Miyano (8). This structure reveals a wealth of information about how retinal is
bound and how the rhodopsin ground state is stabilized. It also shows that critical residues for G
protein activation (E134, R135) are buried and inaccessible to the rod photoreceptor G protein,
transducin (Gt). However, this does not resolve the question of how an activated receptor
activates a G protein, because the structure of the inactive receptor was solved, leaving open the
question of the activation mechanism and the structure of the active receptor. Thus, new
structural approaches are needed to address these questions.
Keywords: GPCRs,
GDP, AIDS, Gt, E134, R135, R*
Introduction
G protein-coupled receptors (GPCRs) form the largest family of membrane proteins responsible
for communication between the cell and the environment. These proteins recognize extracellular
messengers and transducer the signal to the cytosol. GPCRs bind to a wide variety of molecules,
including ions, amino acids, peptides, lipids, and nucleotides. They control the activity of
enzymes, ion channels and vesicular transport, principally through the catalysis of GDP-GTP
exchange on heterotrimeric G proteins. They are involved in diverse biological functions
including the senses of smell, taste and sight, and the regulation of appetite, digestion, blood
pressure, reproduction and inflammation[10] the reason why they are involved in a wide variety
of pathologies. Each cell expresses a few dozen different GPCRs, which implies that its
homeostasis can be influenced by numerous transmitters. A particular GPCR is often expressed
in several tissues. It can be found in the periphery and in the central nervous system. Its roles in
these tissues may be different although the second messengers that result from the initial
activation are probably the same. The organ that is possibly most dependent on GPCR activity is
the brain, where practically all the GPCRs are expressed. They are involved in synaptic
transmission mechanisms and most of our senses depend directly on the activation of specific
GPCRs.GPCRs have proven to be particularly amenable to modulation by small molecule drugs
and are the targets of approximately half of the current prescription drugs, as well as the targets
of a large number of therapeutics and GPCRs provide opportunities for the development of new
drugs with applications in all clinical fields. [11]
Characteristic features of GPCRs
GPCRs are integral membrane proteins with seven Tran’s membrane helices. The N-terminal
segment is extracellular and the C-terminal segment is located in the cytosol. The Trans
membrane (TM) domains are more conserved among GPCRs than the extracellular or
intracellular domains. There are several signature amino acid motifs which provide us with their
identity as GPCRs; for example, the LxxxD motif in the TM II, the DRY motif at the end of the
TM III and the NPxxYmot if on the TM VII (Figure 1). Usually, the intracellular domain III
(between TM V and TM VI) and the carboxyl terminal are considered to play certain roles in Gprotein coupling [11].
GPCRs are divided into families according to their sequence homology. Family A represents the
largest subgroup of receptors and includes catecholamine’s, neuropeptide, chemokine,
glycoprotein’s, lipid and nucleotide receptors. Family A is characterized byseveral highly
conserved amino acids and a disulphide bridge. Most of these receptors also have a
palmitoylatedcysteine in the carboxyl-terminal tail. Ligand binding within the transmembrane
region of the receptor seems to occur mainly in a cavity flanked by TMs III,V, VI and VII. The
crystal structure of rhodopsin [12,13] has indicated that the transmembrane domains ofthis
family are “tilted” and “kinked” (Figure 2a). FamilyB contains receptors for a large number of
peptides such as calcitonin, glucagon, gonadotropin-releasinghormone and parathyroid hormone.
These receptorsare characterized by a relatively long amino terminusthat contains six conserved
cysteine residues, whichpresumably form a network of disulphide bridges(Figure 2b). This
amino terminus seems to play a keyrole for most ligands, but it is not sufficient and
additionalinteractions are found in the extracellular loops.Family C is the metabotropic
containing the metabotropicglutamate receptors, GABA receptors andthe calcium sensor
receptor. These receptors are characterizedby a long amino terminus and carboxyl tail.The amino
terminus is folded as a separate ligandbinding domain which is often described as being likea
“Venus fly trap” (Figure 2c) [10,14,15].
Ligand binding to GPCRs promotes conformational changes leading to G-protein coupling, the
initiation of signal transduction pathways and ultimately cellular response. Studies based on
electron paramagnetic resonance and fluorescence spectroscopy [16] suggested the need of an
outward movement of the cytoplasmic end of TMs III and VI [17, 18], as well asan anticlockwise rotation of TM VI around its helical axis, when viewed from the extracellular side, for
itsactivation. Other helices probably adjust their positions upon activation as well. Each GPCR
has its own selectivity to G proteins(Figure 3), however, the specific sequences activating each G
protein (Gs, Gi, Gq, G12, etc.) are as yet unknown, although there is a proposed theory that basic
amino acids are important for G protein coupling [19].Even though it is known that for many
classes of receptors constitutive or ligand-induced oligomerizationis essential for signaling [20],
only a mono mericmodel for GPCRs is generally accepted. Since the mid-1990s, many reports
have successively shown oligomerizationof the GPCRs, examples of this are the H2histamine
receptor [12] and the β2-adrenergic receptor [21, 22]. Now, oligomerization is widely accepted
as a universal aspect of GPCR biology. After the first reports of GPCR homo-oligomers,it was
shown that some receptor subtypes formed hetero-oligomers, for example AT1-AT2
angiotensinreceptors [23] and A1 adenosine-D1 dopamine receptors[24],
Figure 1. Schematic drawing depicting the 7 helices, the connecting loops and some conserved amino acid motifs in
GPCRs. TheLxxxD motif in the TM II, the DRY motif at the end of the TM III and the NPxxY motif on the TM
VII.
Figure 2. Schematic drawing of the GPCR families. (a) Family A has a short amino terminus and the transmembrane
domainsare “tilted” and ”kinked” (b) Family B has a relatively longamino terminus that contains cysteine residues
(c) Family C hasa long amino terminus folded as a ”Venus fly trap” domain.
Figure 3. Schematic drawing depicting the 7 helices and the
different pathways upon Protein coupling. Each GPCR has its own selectivity to a particular G protein
and each G protein has its own signal pathway
GPCRs in drug discovery
GPCRs have been shown to be excellent targets for pharmaceutical treatments; along with kinases, GPCR
sconstitute the most widely screened classes of signal transduction targets [26]. Many major diseases
involve the malfunction of these receptors making them the most important drug target for
pharmacological intervention .In particular, the subfamily of biogenic amine binding GPCRs has provided
excellent targets for the treatment of several central nervous system diseases, such as schizophrenia
(mixed D2/D1/5-HT2 receptors), psychosis (mixed D2/5-HT2A receptors), depression (5-HT1 receptor),
or migraine (5-HT1 receptor). This GPCR subfamily has also provided drug targets for other disease areas
such as allergies (H1 receptor), asthma (β2 receptor), ulcers (H2 receptor), or
hypertension (α1
antagonist, β1 antagonist [27] (Table 1).GPCR agonist or antagonist drugs have been therapeutically
successful because of their direct activity on the cell surface [28]. GPCRs comprise 50-60% of the drugs
now on the market, including about 25% of the 100 top-selling drugs [29] in commercial terms; GPCRs
will continue to predominate as drug targets. The total human genome
Table 1
Trademark
Generic name
Company
Disease
Clarit in
loratadine
Schering-Plough
Allergies
Zyprexa
Cozaar
Risperdal
Leuplin/ Lupron
Pepcidine
Sereve nt
olanzapine
losartan
risperidone
leuprolide
famotidine
salmat erol
Eli LillyTatemoto
Merk & Co
Johnson & Johnson
Takeda
Merk & Co
GlaxoSmithKline
schizophrenia
hypertension
psychosis
cancer
ulcers
asthma
Diseases related to G protein coupled receptors
Conformational diseases often result from mutations in proteins that are recognized as mis folded
by quality control systems [30,31]. Such recognition can lead to two different phenotypes: some
misfolded proteins can be efficiently ubiquitinated and degraded by the proteasome,leading to a
loss of function [32], whereas othersaccumulate in cells, forming aggregates that can havetoxic
consequences and are often referred to as gain of functions [33]. Studies carried out in the past
decade havelinked these two types of quality control outcomes to theaetiology of a growing list
of congenital and acquiredconformational diseases. In parallel, efforts to overcomethese defects
have led to the development of variousinterventions that successfully rescue proteins from
bothaggregation and degradation pathways. In particular,treatments with chemical compounds
known as eitherchemical or pharmacological chaperones have been foundto stabilize some
conformational mutants, promoting their proper transport to their site of action where, inmany
cases, they can be functional [34–36]. Identifying compounds that can bind to the mutant
proteins hasbeen easier for proteins such as channels and receptorsfor which selective ligands
have already been characterized.Because of their involvement in many pathophysiological
conditions and the rich pharmacological diversitygenerated through various drug screening
campaigns-protein-coupled receptors (GPCRs) have attractedconsiderable attention for the
identification of pharmacologicalchaperones. At least ten congenital diseases havebeen linked to
mutations in GPCRs that lead to the irretention in the endoplasmic reticulum (ER) (Table 3),and
pharmacological chaperones have been identified for three of these Here, we reviewthestudies
thatled to the discovery of these potential therapeutic agents,with a special emphasis on their
proposedmechanismsof action
GPCR involved in conformational diseases
Table 3
GPCR
Diseases
Adrenocorticotropic hormone receptor
Familial adrenocorticotropic hormone
resistance
Familial hypocalciuric hypocalcaemia
Hirsch sprung disease
Hypogonadotropic hypogonadism
Male pseudohermaphroditism
Obesity
Calcium sensing receptor
Endothelia-B
GnRHR
Luteinizing hormone receptor
Melanocortin 4 receptor
Conclusion
GPCRs are regarded as the most important molecules in the field of drug discovery and design,
their role as receptors in many of the basic processes on the organism and their presence on the
surface of cells on all tissues make them excellent targets. Much effort is needed, however, in the
deorphanization of GPCRs, matching all currently known molecules with a Ligand. There are
several initiatives in this field, but their difficulty makes the progress very slow. Despite of the fact that
the structure of a single family is known, research has progressed, using combined
structurebasedtechniques. There are several groupsattemptingto purify, fold and crystallize GPCRs with
important breakthroughs, and structures could be expected in the near future.
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