G protein–coupled receptors (GPCRs), also known as
seven-(pass)-transmembrane domain receptors, 7TM receptors,
heptahelical receptors, serpentine receptor, and G protein–linked
receptors (GPLR), constitute a large protein family of receptors that
detect molecules outside the cell and activate internal signal
transduction pathways and, ultimately, cellular responses. Coupling
with G proteins, they are called seven-transmembrane receptors because
they pass through the cell membrane seven times.
G protein–coupled receptors are found only in eukaryotes, including
yeast, choanoflagellates, and animals. The ligands that bind and
activate these receptors include light-sensitive compounds, odors,
pheromones, hormones, and neurotransmitters, and vary in size from
small molecules to peptides to large proteins. G protein–coupled
receptors are involved in many diseases, and are also the target of
approximately 34% of all modern medicinal drugs.
There are two principal signal transduction pathways involving the G
the cAMP signal pathway and
the phosphatidylinositol signal pathway.
When a ligand binds to the GPCR it causes a conformational change in
the GPCR, which allows it to act as a guanine nucleotide exchange
factor (GEF). The GPCR can then activate an associated
G protein by
exchanging the GDP bound to the
G protein for a GTP. The G protein's
α subunit, together with the bound GTP, can then dissociate from the
β and γ subunits to further affect intracellular signaling proteins
or target functional proteins directly depending on the α subunit
type (Gαs, Gαi/o, Gαq/11, Gα12/13).:1160
1 History and significance
4 Receptor structure
5 Structure-function relationships
6.1 Ligand binding
6.2 Conformational change
6.3 G-protein activation/deactivation cycle
7.1 G-protein-dependent signaling
7.1.1 Gα signaling
7.1.2 Gβγ signaling
7.2 G-protein-independent signaling
7.2.2 GPCR-independent signaling by heterotrimeric G-proteins
8 Details of cAMP and PIP2 pathways
8.1 cAMP signal pathway
Phosphatidylinositol signal pathway
9 Receptor regulation
Phosphorylation by cAMP-dependent protein kinases
Phosphorylation by GRKs
9.3 Mechanisms of GPCR signal termination
9.4 GPCR cellular regulation
10 Receptor oligomerization
11 Origin and diversification of the superfamily
12 See also
14 Further reading
15 External links
History and significance
Nobel Prize in Chemistry
Nobel Prize in Chemistry was awarded to
Brian Kobilka and
Robert Lefkowitz for their work that was "crucial for understanding
how G protein–coupled receptors function". There have been at
least seven other Nobel Prizes awarded for some aspect of G
protein–mediated signaling. As of 2012, two of the
top ten global best-selling drugs (Advair Diskus and Abilify) act by
targeting G protein–coupled receptors.
Classification Scheme of GPCRs. Class A (Rhodopsin-like), Class B
(Secretin-like), Class C (
Glutamate Receptor-like), Others (Adhesion
Frizzled (11), Taste type-2 (25), unclassified (23)).
The exact size of the GPCR superfamily is unknown, but nearly 800
different human genes (or ~ 4% of the entire protein-coding genome)
have been predicted to code for them from genome sequence
analysis. Although numerous classification schemes have been
proposed, the superfamily was classically divided into three main
classes (A, B and C) with no detectable shared sequence homology
The largest class by far is class A, which accounts for nearly 85% of
the GPCR genes. Of class A GPCRs, over half of these are predicted to
encode olfactory receptors, while the remaining receptors are liganded
by known endogenous compounds or are classified as orphan receptors.
Despite the lack of sequence homology between classes, all GPCRs have
a common structure and mechanism of signal transduction. The very
large rhodopsin A group has been further subdivided into 19 subgroups
More recently, an alternative classification system called GRAFS
(Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been
proposed. According to the classical A-F system, GPCRs can be
grouped into 6 classes based on sequence homology and functional
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (
Secretin receptor family)
Class C (or 3) (
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (
Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)
An early study based on available DNA sequence suggested that the
human genome encodes roughly 750 G protein–coupled receptors,
about 350 of which detect hormones, growth factors, and other
endogenous ligands. Approximately 150 of the GPCRs found in the human
genome have unknown functions.
Some web-servers and bioinformatics prediction methods
have been used for predicting the classification of GPCRs according to
their amino acid sequence alone, by means of the pseudo amino acid
GPCRs are involved in a wide variety of physiological processes. Some
examples of their physiological roles include:
The visual sense: The opsins use a photoisomerization reaction to
translate electromagnetic radiation into cellular signals. Rhodopsin,
for example, uses the conversion of 11-cis-retinal to
all-trans-retinal for this purpose
The gustatory sense (taste): GPCRs in taste cells mediate release of
gustducin in response to bitter- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind
odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind
several different neurotransmitters, including serotonin, dopamine,
GABA, and glutamate
Regulation of immune system activity and inflammation: Chemokine
receptors bind ligands that mediate intercellular communication
between cells of the immune system; receptors such as histamine
receptors bind inflammatory mediators and engage target cell types in
the inflammatory response. GPCRs are also involved in
immune-modulation and directly involved in suppression of TLR-induced
immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and
parasympathetic nervous systems are regulated by GPCR pathways,
responsible for control of many automatic functions of the body such
as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density
Homeostasis modulation (e.g., water balance).
Involved in growth and metastasis of some types of tumors.
GPCRs are integral membrane proteins that possess seven
membrane-spanning domains or transmembrane helices. The
extracellular parts of the receptor can be glycosylated. These
extracellular loops also contain two highly conserved cysteine
residues that form disulfide bonds to stabilize the receptor
structure. Some seven-transmembrane helix proteins (channelrhodopsin)
that resemble GPCRs may contain ion channels, within their protein.
Similar to GPCRs, the adiponectin receptors 1 and 2 (
ADIPOR2) also possess 7 transmembrane domains. However,
ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs
usually have an extracellular N-terminus, cytoplasmic C-terminus,
whereas ADIPORs are inverted) and do not associate with G
Early structural models for GPCRs were based on their weak analogy to
bacteriorhodopsin, for which a structure had been determined by both
electron diffraction (PDB: 2BRD, 1AT9) and X ray-based
crystallography (1AP9). In 2000, the first crystal structure of
a mammalian GPCR, that of bovine rhodopsin (1F88), was solved.
While the main feature, the seven-transmembrane helices, is conserved,
the relative orientation of the helices differ significantly from that
of bacteriorhodopsin. In 2007, the first structure of a human GPCR was
solved (2R4R, 2R4S). This was followed immediately by a
higher resolution structure of the same receptor (2RH1).
This human β2-adrenergic receptor GPCR structure proved highly
similar to the bovine rhodopsin in terms of the relative orientation
of the seven-transmembrane helices. However, the conformation of the
second extracellular loop is entirely different between the two
structures. Since this loop constitutes the "lid" that covers the top
of the ligand binding site, this conformational difference highlights
the difficulties in constructing homology models of other GPCRs based
only on the rhodopsin structure.
The structures of activated or agonist-bound GPCRs have also been
determined. These structures indicate how ligand
binding at the extracellular side of a receptor leads to
conformational changes in the cytoplasmic side of the receptor. The
biggest change is an outward movement of the cytoplasmic part of the
5th and 6th transmembrane helix (TM5 and TM6). The structure of
activated beta-2 adrenergic receptor in complex with Gs confirmed that
the Gα binds to a cavity created by this movement.
A structure database, GPCR-HGmod, was recently constructed which
contains 3D structural models of all human G-protein coupled
receptors, built by the GPCR-
I-TASSER pipeline through homology
modeling and ab initio structure prediction.
Two-dimensional schematic of a generic GPCR set in a
Lipid Raft. Click
the image for higher resolution to see details regarding the locations
of important structures.
In terms of structure, GPCRs are characterized by an extracellular
N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to
TM-7) connected by three intracellular (IL-1 to IL-3) and three
extracellular loops (EL-1 to EL-3), and finally an intracellular
C-terminus. The GPCR arranges itself into a tertiary structure
resembling a barrel, with the seven transmembrane helices forming a
cavity within the plasma membrane that serves a ligand-binding domain
that is often covered by EL-2. Ligands may also bind elsewhere,
however, as is the case for bulkier ligands (e.g., proteins or large
peptides), which instead interact with the extracellular loops, or, as
illustrated by the class C metabotropic glutamate receptors (mGluRs),
the N-terminal tail. The class C GPCRs are distinguished by their
large N-terminal tail, which also contains a ligand-binding domain.
Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a
conformational change that leads to its interaction with the residues
of the extracellular loops and TM domains. The eventual effect of all
three types of agonist-induced activation is a change in the relative
orientations of the TM helices (likened to a twisting motion) leading
to a wider intracellular surface and "revelation" of residues of the
intracellular helices and TM domains crucial to signal transduction
function (i.e., G-protein coupling).
Inverse agonists and antagonists
may also bind to a number of different sites, but the eventual effect
must be prevention of this TM helix reorientation.
The structure of the N- and
C-terminal tails of GPCRs may also serve
important functions beyond ligand-binding. For example, The C-terminus
of M3 muscarinic receptors is sufficient, and the six-amino-acid
polybasic (KKKRRK) domain in the
C-terminus is necessary for its
preassembly with Gq proteins. In particular, the
contains serine (Ser) or threonine (Thr) residues that, when
phosphorylated, increase the affinity of the intracellular surface for
the binding of scaffolding proteins called β-arrestins (β-arr).
Once bound, β-arrestins both sterically prevent G-protein coupling
and may recruit other proteins, leading to the creation of signaling
complexes involved in extracellular-signal regulated kinase (ERK)
pathway activation or receptor endocytosis (internalization). As the
phosphorylation of these Ser and Thr residues often occurs as a result
of GPCR activation, the β-arr-mediated G-protein-decoupling and
internalization of GPCRs are important mechanisms of
desensitization. In addition, internalized "mega-complexes"
consisting of a single GPCR, β-arr(in the tail conformation),
G protein exist and may account for protein
signaling from endosomes.
A final common structural theme among GPCRs is palmitoylation of one
or more sites of the
C-terminal tail or the intracellular loops.
Palmitoylation is the covalent modification of cysteine (Cys) residues
via addition of hydrophobic acyl groups, and has the effect of
targeting the receptor to cholesterol- and sphingolipid-rich
microdomains of the plasma membrane called lipid rafts. As many of the
downstream transducer and effector molecules of GPCRs (including those
involved in negative feedback pathways) are also targeted to lipid
rafts, this has the effect of facilitating rapid receptor signaling.
GPCRs respond to extracellular signals mediated by a huge diversity of
agonists, ranging from proteins to biogenic amines to protons, but all
transduce this signal via a mechanism of G-protein coupling. This is
made possible by a guanine-nucleotide exchange factor (GEF) domain
primarily formed by a combination of IL-2 and IL-3 along with adjacent
residues of the associated TM helices.
Cartoon depicting the basic concept of GPCR Conformational Activation.
Ligand binding disrupts an ionic lock between the E/DRY motif of TM-3
and acidic residues of TM-6. As a result, the GPCR reorganizes to
allow activation of G-alpha proteins. The side perspective is a view
from above and to the side of the GPCR as it is set in the plasma
membrane (the membrane lipids have been omitted for clarity). The
intracellular perspective shows the view looking up at the plasma
membrane from inside the cell.
G protein–coupled receptor
G protein–coupled receptor is activated by an external signal in
the form of a ligand or other signal mediator. This creates a
conformational change in the receptor, causing activation of a G
protein. Further effect depends on the type of G protein. G proteins
are subsequently inactivated by
GTPase activating proteins, known as
GPCRs include: receptors for sensory signal mediators (e.g., light and
olfactory stimulatory molecules); adenosine, bombesin, bradykinin,
endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor
(HGF), melanocortins, neuropeptide Y, opioid peptides, opsins,
somatostatin, GH, tachykinins, members of the vasoactive intestinal
peptide family, and vasopressin; biogenic amines (e.g., dopamine,
epinephrine, norepinephrine, histamine, glutamate (metabotropic
effect), glucagon, acetylcholine (muscarinic effect), and serotonin);
chemokines; lipid mediators of inflammation (e.g., prostaglandins,
prostanoids, platelet-activating factor, and leukotrienes); and
peptide hormones (e.g., calcitonin, C5a anaphylatoxin,
follicle-stimulating hormone (FSH), gonadotropin-releasing hormone
(GnRH), neurokinin, thyrotropin-releasing hormone (TRH), cannabinoids,
and oxytocin). GPCRs that act as receptors for stimuli that have not
yet been identified are known as orphan receptors.
However, in other types of receptors that have been studied, wherein
ligands bind externally to the membrane, the ligands of GPCRs
typically bind within the transmembrane domain. However,
protease-activated receptors are activated by cleavage of part of
their extracellular domain.
Crystal structure of activated beta-2 adrenergic receptor in complex
with Gs(PDB entry 3SN6). The receptor is colored red, Gα green, Gβ
cyan, and Gγ yellow. The
C-terminus of Gα is located in a cavity
created by an outward movement of the cytoplasmic parts of TM5 and 6.
The transduction of the signal through the membrane by the receptor is
not completely understood. It is known that in the inactive state, the
GPCR is bound to a heterotrimeric
G protein complex. Binding of an
agonist to the GPCR results in a conformational change in the receptor
that is transmitted to the bound Gα subunit of the heterotrimeric G
protein via protein domain dynamics. The activated Gα subunit
exchanges GTP in place of GDP which in turn triggers the dissociation
of Gα subunit from the Gβγ dimer and from the receptor. The
dissociated Gα and Gβγ subunits interact with other intracellular
proteins to continue the signal transduction cascade while the freed
GPCR is able to rebind to another heterotrimeric
G protein to form a
new complex that is ready to initiate another round of signal
It is believed that a receptor molecule exists in a conformational
equilibrium between active and inactive biophysical states. The
binding of ligands to the receptor may shift the equilibrium toward
the active receptor states. Three types of ligands exist: Agonists are
ligands that shift the equilibrium in favour of active states; inverse
agonists are ligands that shift the equilibrium in favour of inactive
states; and neutral antagonists are ligands that do not affect the
equilibrium. It is not yet known how exactly the active and inactive
states differ from each other.
G-protein activation/deactivation cycle
Cartoon depicting the
Heterotrimeric G-protein activation/deactivation
cycle in the context of GPCR signaling
See also: G protein
When the receptor is inactive, the GEF domain may be bound to an also
inactive α-subunit of a heterotrimeric G-protein. These "G-proteins"
are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ,
respectively) that is rendered inactive when reversibly bound to
Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide)
but active when bound to
Guanosine triphosphate (GTP). Upon receptor
activation, the GEF domain, in turn, allosterically activates the
G-protein by facilitating the exchange of a molecule of GDP for GTP at
the G-protein's α-subunit. The cell maintains a 10:1 ratio of
cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the
subunits of the G-protein dissociate from the receptor, as well as
each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ
dimer, which are now free to modulate the activity of other
intracellular proteins. The extent to which they may diffuse, however,
is limited due to the palmitoylation of Gα and the presence of an
isoprenoid moiety that has been covalently added to the C-termini of
Because Gα also has slow GTP→GDP hydrolysis capability, the
inactive form of the α-subunit (Gα-GDP) is eventually regenerated,
thus allowing reassociation with a Gβγ dimer to form the "resting"
G-protein, which can again bind to a GPCR and await activation. The
rate of GTP hydrolysis is often accelerated due to the actions of
another family of allosteric modulating proteins called Regulators of
G-protein Signaling, or RGS proteins, which are a type of
GTPase-Activating Protein, or GAP. In fact, many of the primary
effector proteins (e.g., adenylate cyclases) that become
activated/inactivated upon interaction with Gα-GTP also have GAP
activity. Thus, even at this early stage in the process,
GPCR-initiated signaling has the capacity for self-termination.
Proposed downstream interactions between integrin signaling and GPCRs.
Integrins are shown elevating
Ca2+ and phosphorylating FAK, which is
weakening GPCR signaling.
GPCRs downstream signals have been shown to possibly interact with
integrin signals, such as FAK.
Integrin signaling will
phosphorylate FAK, which can then decrease GPCR
G-protein-coupled receptor mechanism
If a receptor in an active state encounters a G protein, it may
activate it. Some evidence suggests that receptors and G proteins are
actually pre-coupled. For example, binding of G proteins to
receptors affects the receptor's affinity for ligands. Activated G
proteins are bound to GTP.
Further signal transduction depends on the type of G protein. The
enzyme adenylate cyclase is an example of a cellular protein that can
be regulated by a G protein, in this case the
G protein Gs. Adenylate
cyclase activity is activated when it binds to a subunit of the
activated G protein. Activation of adenylate cyclase ends when the G
protein returns to the GDP-bound state.
Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms
are known in humans) may also be activated or inhibited in other ways
Calmodulin binding), which can modify the activity of
these enzymes in an additive or synergistic fashion along with the G
The signaling pathways activated through a GPCR are limited by the
primary sequence and tertiary structure of the GPCR itself but
ultimately determined by the particular conformation stabilized by a
particular ligand, as well as the availability of transducer
molecules. Currently, GPCRs are considered to utilize two primary
types of transducers:
G-proteins and β-arrestins. Because β-arr's
have high affinity only to the phosphorylated form of most GPCRs (see
above or below), the majority of signaling is ultimately dependent
upon G-protein activation. However, the possibility for interaction
does allow for G-protein-independent signaling to occur.
There are three main G-protein-mediated signaling pathways, mediated
by four sub-classes of
G-proteins distinguished from each other by
sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each
sub-class of G-protein consists of multiple proteins, each the product
of multiple genes or splice variations that may imbue them with
differences ranging from subtle to distinct with regard to signaling
properties, but in general they appear reasonably grouped into four
classes. Because the signal transducing properties of the various
possible βγ combinations do not appear to radically differ from one
another, these classes are defined according to the isoform of their
While most GPCRs are capable of activating more than one Gα-subtype,
they also show a preference for one subtype over another. When the
subtype activated depends on the ligand that is bound to the GPCR,
this is called functional selectivity (also known as agonist-directed
trafficking, or conformation-specific agonism). However, the binding
of any single particular agonist may also initiate activation of
multiple different G-proteins, as it may be capable of stabilizing
more than one conformation of the GPCR's GEF domain, even over the
course of a single interaction. In addition, a conformation that
preferably activates one isoform of Gα may activate another if the
preferred is less available. Furthermore, feedback pathways may result
in receptor modifications (e.g., phosphorylation) that alter the
G-protein preference. Regardless of these various nuances, the GPCR's
preferred coupling partner is usually defined according to the
G-protein most obviously activated by the endogenous ligand under most
physiological or experimental conditions.
The effector of both the
Gαs and Gαi/o pathways is the
cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate
cyclase, or AC. While there are ten different AC gene products in
mammals, each with subtle differences in tissue distribution or
function, all catalyze the conversion of cytosolic adenosine
triphosphate (ATP) to cAMP, and all are directly stimulated by
G-proteins of the
Gαs class. In contrast, however, interaction with
Gα subunits of the Gαi/o type inhibits AC from generating cAMP.
Thus, a GPCR coupled to
Gαs counteracts the actions of a GPCR coupled
to Gαi/o, and vice versa. The level of cytosolic cAMP may then
determine the activity of various ion channels as well as members of
the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is
considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ),
which catalyzes the cleavage of membrane-bound phosphatidylinositol
4,5-biphosphate (PIP2) into the second messengers inositol (1,4,5)
trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3
receptors found in the membrane of the endoplasmic reticulum (ER) to
Ca2+ release from the ER, while DAG diffuses along the plasma
membrane where it may activate any membrane localized forms of a
second ser/thr kinase called protein kinase C (PKC). Since many
isoforms of PKC are also activated by increases in intracellular Ca2+,
both these pathways can also converge on each other to signal through
the same secondary effector. Elevated intracellular
Ca2+ also binds
and allosterically activates proteins called calmodulins, which in
turn go on to bind and allosterically activate enzymes such as
Ca2+/calmodulin-dependent kinases (CAMKs).
The effectors of the Gα12/13 pathway are three RhoGEFs (p115-RhoGEF,
PDZ-RhoGEF, and LARG), which, when bound to Gα12/13 allosterically
activate the cytosolic small GTPase, Rho. Once bound to GTP, Rho can
then go on to activate various proteins responsible for cytoskeleton
regulation such as Rho-kinase (ROCK). Most GPCRs that couple to
Gα12/13 also couple to other sub-classes, often Gαq/11.
The above descriptions ignore the effects of Gβγ–signalling, which
can also be important, in particular in the case of activated
Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion
channels, such as G-protein-regulated inwardly rectifying K+ channels
(GIRKs), P/Q- and N-type voltage-gated
Ca2+ channels, as well as some
isoforms of AC and PLC, along with some phosphoinositide-3-kinase
Although they are classically thought of working only together, GPCRs
may signal through G-protein-independent mechanisms, and
G-proteins may play functional roles independent of
GPCRs. GPCRs may signal independently through many proteins already
mentioned for their roles in G-protein-dependent signaling such as
β-arrs, GRKs, and Srcs. In addition, further scaffolding proteins
involved in subcellular localization of GPCRs (e.g.,
PDZ-domain-containing proteins) may also act as signal transducers.
Most often the effector is a member of the
In the late 1990s, evidence began accumulating to suggest that some
GPCRs are able to signal without G proteins. The ERK2
mitogen-activated protein kinase, a key signal transduction mediator
downstream of receptor activation in many pathways, has been shown to
be activated in response to cAMP-mediated receptor activation in the
slime mold D. discoideum despite the absence of the associated G
protein α- and β-subunits.
In mammalian cells, the much-studied β2-adrenoceptor has been
demonstrated to activate the ERK2 pathway after arrestin-mediated
uncoupling of G-protein-mediated signaling. Therefore, it seems likely
that some mechanisms previously believed related purely to receptor
desensitisation are actually examples of receptors switching their
signaling pathway, rather than simply being switched off.
In kidney cells, the bradykinin receptor B2 has been shown to interact
directly with a protein tyrosine phosphatase. The presence of a
tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory
motif) sequence in the B2 receptor is necessary to mediate this
interaction and subsequently the antiproliferative effect of
GPCR-independent signaling by heterotrimeric G-proteins
Although it is a relatively immature area of research, it appears that
G-proteins may also take part in non-GPCR signaling.
There is evidence for roles as signal transducers in nearly all other
types of receptor-mediated signaling, including integrins, receptor
tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as
modulation of various other "accessory" proteins such as GEFs,
guanine-nucleotide dissociation inhibitors (GDIs) and protein
phosphatases. There may even be specific proteins of these classes
whose primary function is as part of GPCR-independent pathways, termed
activators of G-protein signalling (AGS). Both the ubiquity of these
interactions and the importance of Gα vs. Gβγ subunits to these
processes are still unclear.
Details of cAMP and PIP2 pathways
Activation effects of cAMP on protein kinase A
The effect of Rs and Gs in cAMP signal pathway
The effect of Ri and Gi in cAMP signal pathway
There are two principal signal transduction pathways involving the G
protein-linked receptors: the cAMP signal pathway and the
phosphatidylinositol signal pathway.
cAMP signal pathway
Main article: cAMP-dependent pathway
The cAMP signal transduction contains 5 main characters: stimulative
hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative
regulative G-protein (Gs) or inhibitory regulative G-protein (Gi);
adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.
Stimulative hormone receptor (Rs) is a receptor that can bind with
stimulative signal molecules, while inhibitory hormone receptor (Ri)
is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein linked to stimulative
hormone receptor (Rs), and its α subunit upon activation could
stimulate the activity of an enzyme or other intracellular metabolism.
On the contrary, inhibitory regulative G-protein is linked to an
inhibitory hormone receptor, and its α subunit upon activation could
inhibit the activity of an enzyme or other intracellular metabolism.
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes ATP
to form cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced
is a second messenger in cellular metabolism and is an allosteric
activator of protein kinase A.
Protein kinase A is an important enzyme in cell metabolism due to its
ability to regulate cell metabolism by phosphorylating specific
committed enzymes in the metabolic pathway. It can also regulate
specific gene expression, cellular secretion, and membrane
permeability. The protein enzyme contains two catalytic subunits and
two regulatory subunits. When there is no cAMP，the complex is
inactive. When cAMP binds to the regulatory subunits, their
conformation is altered, causing the dissociation of the regulatory
subunits, which activates protein kinase A and allows further
These signals then can be terminated by cAMP phosphodiesterase, which
is an enzyme that degrades cAMP to 5'-AMP and inactivates protein
Phosphatidylinositol signal pathway
Main article: IP3/DAG pathway
In the phosphatidylinositol signal pathway, the extracellular signal
molecule binds with the G-protein receptor (Gq) on the cell surface
and activates phospholipase C, which is located on the plasma
membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate
(PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3)
and diacylglycerol (DAG). IP3 binds with the
IP3 receptor in the
membrane of the smooth endoplasmic reticulum and mitochondria to open
Ca2+ channels. DAG helps activate protein kinase C (PKC), which
phosphorylates many other proteins, changing their catalytic
activities, leading to cellular responses.
The effects of
Ca2+ are also remarkable: it cooperates with DAG in
activating PKC and can activate the CaM kinase pathway, in which
calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a
change in conformation, and activates CaM kinase II, which has unique
ability to increase its binding affinity to CaM by
autophosphorylation, making CaM unavailable for the activation of
other enzymes. The kinase then phosphorylates target enzymes,
regulating their activities. The two signal pathways are connected
together by Ca2+-CaM, which is also a regulatory subunit of adenylyl
cyclase and phosphodiesterase in the cAMP signal pathway.
GPCRs become desensitized when exposed to their ligand for a long
period of time. There are two recognized forms of desensitization: 1)
homologous desensitization, in which the activated GPCR is
downregulated; and 2) heterologous desensitization, wherein the
activated GPCR causes downregulation of a different GPCR. The key
reaction of this downregulation is the phosphorylation of the
intracellular (or cytoplasmic) receptor domain by protein kinases.
Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated
by the signal chain coming from the
G protein (that was activated by
the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a
feedback mechanism, these activated kinases phosphorylate the
receptor. The longer the receptor remains active the more kinases are
activated and the more receptors are phosphorylated. In
β2-adrenoceptors, this phosphorylation results in the switching of
the coupling from the Gs class of G-protein to the Gi class.
cAMP-dependent PKA mediated phosphorylation can cause heterologous
desensitisation in receptors other than those activated.
Phosphorylation by GRKs
G protein-coupled receptor kinases
G protein-coupled receptor kinases (GRKs) are protein kinases that
phosphorylate only active GPCRs. G-protein-coupled receptor
kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR)
signaling. They constitute a family of seven mammalian
serine-threonine protein kinases that phosphorylate agonist-bound
receptor. GRKs-mediated receptor phosphorylation rapidly initiates
profound impairment of receptor signaling and desensitization.
Activity of GRKs and subcellular targeting is tightly regulated by
interaction with receptor domains,
G protein subunits, lipids,
anchoring proteins and calcium-sensitive proteins.
Phosphorylation of the receptor can have two consequences:
Translocation: The receptor is, along with the part of the membrane it
is embedded in, brought to the inside of the cell, where it is
dephosphorylated within the acidic vesicular environment and then
brought back. This mechanism is used to regulate long-term exposure,
for example, to a hormone, by allowing resensitisation to follow
desensitisation. Alternatively, the receptor may undergo lysozomal
degradation, or remain internalised, where it is thought to
participate in the initiation of signalling events, the nature of
which depending on the internalised vesicle's subcellular
Arrestin linking: The phosphorylated receptor can be linked to
arrestin molecules that prevent it from binding (and activating) G
proteins, in effect switching it off for a short period of time. This
mechanism is used, for example, with rhodopsin in retina cells to
compensate for exposure to bright light. In many cases, arrestin's
binding to the receptor is a prerequisite for translocation. For
example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor
for binding with clathrin, and with the beta-subunit of AP2 (clathrin
adaptor molecules); thus, the arrestin here acts as a scaffold
assembling the components needed for clathrin-mediated endocytosis of
Mechanisms of GPCR signal termination
As mentioned above,
G-proteins may terminate their own activation due
to their intrinsic GTP→GDP hydrolysis capability. However, this
reaction proceeds at a slow rate (≈.02 times/sec) and, thus, it
would take around 50 seconds for any single G-protein to deactivate if
other factors did not come into play. Indeed, there are around 30
isoforms of RGS proteins that, when bound to Gα through their GAP
domain, accelerate the hydrolysis rate to ≈30 times/sec. This
1500-fold increase in rate allows for the cell to respond to external
signals with high speed, as well as spatial resolution due to limited
amount of second messenger that can be generated and limited distance
a G-protein can diffuse in .03 seconds. For the most part, the RGS
proteins are promiscuous in their ability to activate G-proteins,
while which RGS is involved in a given signaling pathway seems more
determined by the tissue and GPCR involved than anything else. In
addition, RGS proteins have the additional function of increasing the
rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further
contributing to the time resolution of GPCR signaling.
In addition, the GPCR may be desensitized itself. This can occur as:
a direct result of ligand occupation, wherein the change in
conformation allows recruitment of GPCR-Regulating Kinases (GRKs),
which go on to phosphorylate various serine/threonine residues of IL-3
C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity
for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at
which point β-arrestin may bind and act to both sterically hinder
G-protein coupling as well as initiate the process of receptor
internalization through clathrin-mediated endocytosis. Because only
the liganded receptor is desensitized by this mechanism, it is called
the affinity for β-arrestin may be increased in a ligand occupation
and GRK-independent manner through phosphorylation of different
ser/thr sites (but also of IL-3 and the
C-terminal tail) by PKC and
PKA. These phosphorylations are often sufficient to impair G-protein
coupling on their own as well.
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR
phosphorylation and β-arrestin binding in an occupation-independent
manner. These latter two mechanisms allow for desensitization of one
GPCR due to the activities of others, or heterologous desensitization.
GRKs may also have GAP domains and so may contribute to inactivation
through non-kinase mechanisms as well. A combination of these
mechanisms may also occur.
Once β-arrestin is bound to a GPCR, it undergoes a conformational
change allowing it to serve as a scaffolding protein for an adaptor
complex termed AP-2, which in turn recruits another protein called
clathrin. If enough receptors in the local area recruit clathrin in
this manner, they aggregate and the membrane buds inwardly as a result
of interactions between the molecules of clathrin, in a process called
opsonization. Once the pit has been pinched off the plasma membrane
due to the actions of two other proteins called amphiphysin and
dynamin, it is now an endocytic vesicle. At this point, the adapter
molecules and clathrin have dissociated, and the receptor is either
trafficked back to the plasma membrane or targeted to lysosomes for
At any point in this process, the β-arrestins may also recruit other
proteins—such as the non-receptor tyrosine kinase (nRTK),
c-SRC—which may activate ERK1/2, or other mitogen-activated protein
kinase (MAPK) signaling through, for example, phosphorylation of the
small GTP-ase, Ras, or recruit the proteins of the ERK cascade
directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is
initiated due to their close proximity to one another. Another target
of c-SRC are the dynamin molecules involved in endocytosis. Dynamins
polymerize around the neck of an incoming vesicle, and their
phosphorylation by c-SRC provides the energy necessary for the
conformational change allowing the final "pinching off" from the
GPCR cellular regulation
Receptor desensitization is mediated through a combination
phosphorylation, β-arr binding, and endocytosis as described above.
Downregulation occurs when endocytosed receptor is embedded in an
endosome that is trafficked to merge with an organelle called a
lysosome. Because lysosomal membranes are rich in proton pumps, their
interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to
denature the GPCRs. In addition, lysosomes contain many degradative
enzymes, including proteases, which can function only at such low pH,
and so the peptide bonds joining the residues of the GPCR together may
be cleaved. Whether or not a given receptor is trafficked to a
lysosome, detained in endosomes, or trafficked back to the plasma
membrane depends on a variety of factors, including receptor type and
magnitude of the signal. GPCR regulation is additionally mediated by
gene transcription factors. These factors can increase or decrease
gene transcription and thus increase or decrease the generation of new
receptors (up- or down-regulation) that travel to the cell membrane.
Main article: GPCR oligomer
G-protein-coupled receptor oligomerisation is a widespread phenomenon.
One of the best-studied examples is the metabotropic GABAB receptor.
This so-called constitutive receptor is formed by heterodimerization
of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the
GABABR2 in heterologous systems leads to retention of the subunit in
the endoplasmic reticulum. Expression of the GABABR2 subunit alone,
meanwhile, leads to surface expression of the subunit, although with
no functional activity (i.e., the receptor does not bind agonist and
cannot initiate a response following exposure to agonist). Expression
of the two subunits together leads to plasma membrane expression of
functional receptor. It has been shown that GABABR2 binding to GABABR1
causes masking of a retention signal of functional receptors.
Origin and diversification of the superfamily
Signal transduction mediated by the superfamily of GPCRs dates back to
the origin of multicellularity. Mammalian-like GPCRs are found in
fungi, and have been classified according to the
system based on GPCR fingerprints. Identification of the
superfamily members across the eukaryotic domain, and comparison of
the family-specific motifs, have shown that the superfamily of GPCRs
have a common origin. Characteristic motifs indicate that three of
GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved
Dictyostelium discoideum cAMP receptors before the split of
Opisthokonts. Later, the
Secretin family evolved from the Adhesion
GPCR receptor family before the split of nematodes.
G protein-coupled receptors
G protein-coupled receptors database
List of MeSH codes (D12.776)
Pepducins, a class of drug candidates targeted at GPCRs
Receptor activated solely by a synthetic ligand, a technique for
control of cell signaling through synthetic GPCRs
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"GPCR Reference Library". Retrieved 11 August 2008. Reference for
molecular and mathematical models for the initial receptor
Nobel Prize in Chemistry
Nobel Prize in Chemistry 2012" (PDF). Retrieved 10 October
Wikimedia Commons has media related to
G protein coupled receptors.
G-protein-coupled receptors at the US National Library of Medicine
Medical Subject Headings (MeSH)
GPCR Cell Line
"GPCR Database". IUPHAR Database. International Union of Basic and
Clinical Pharmacology. Retrieved 11 August 2008.
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(GPCRs). ; Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K,
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"G Protein-Coupled Receptors on the NET". Retrieved 10 November 2010.
a classification of GPCRs
"PSI GPCR Network Center". Retrieved 11 July 2013. a
Initiative:Biology Network Center aimed at determining the 3D
structures of representative GPCR family proteins
Membrane proteins, receptors: cell surface receptors
G protein–coupled receptor
Eicosanoid receptor (Prostaglandin receptor)
Biogenic amine receptor
Metabotropic glutamate receptor
Ligand-gated ion channel
Serine/threonine-specific protein kinase
Receptor tyrosine kinase
Tumor necrosis factor receptor
Lipoprotein receptor-related protein
Progestin and adipoQ receptor
Cell surface receptor: G protein–coupled receptors
Class A: Rhodopsin-like
(all but 5-HT3) 5-HT1 (A
2), EP (1
CB2, GPR (18
Free fatty acid (1
Lysophosphatidic acid (1
Formyl peptide (1
Gonadotropin-releasing hormone (1
Nociceptin & Zeta, but not Sigma)
Class B: Secretin-like
Brain-specific angiogenesis inhibitor (1
Corticotropin-releasing hormone (1
Parathyroid hormone (1
Vasoactive intestinal peptide
Vasoactive intestinal peptide (1
Metabotropic glutamate / pheromone
Glutamate receptor (
Metabotropic glutamate (1
Frizzled / Smoothened