G protein-coupled receptor

guanine nucleotide exchange factor (GEF). The GPCR

can then activate an associated G protein by exchanging
its bound GDP for a GTP. The G proteins subunit, together with the bound GTP, can then dissociate from the
and subunits to further aect intracellular signaling
proteins or target functional proteins directly depending
on the subunit type (G , G/, G /, G/).[7]:1160

1 Classication

The seven-transmembrane -helix structure of a G protein

coupled receptor

G proteincoupled receptors (GPCRs), also known as

seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and
G proteinlinked receptors (GPLR), constitute a large
protein family of receptors that sense molecules outside
the cell and activate inside signal transduction pathways
and, ultimately, cellular responses. They are called seventransmembrane receptors because they pass through the Classication Scheme of GPCRs. Class A (Rhodopsin-like),
Class B (Secretin-like),Class C (Glutamate Receptor-like), Othcell membrane seven times.

ers (Adhesion (33), Frizzled (11), Taste type-2 (25), unclassied

(23)).[8]

G proteincoupled receptors are found only in

eukaryotes, including yeast, choanoagellates,[2]
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 proteincoupled receptors are involved in
many diseases, and are also the target of approximately
40% of all modern medicinal drugs.[3][4] The 2012
Nobel Prize in Chemistry was awarded to Brian Kobilka
and Robert Lefkowitz for their work that was crucial
for understanding how G proteincoupled receptors
function..[5] There have been at least seven other Nobel
Prizes awarded for some aspect of G proteinmediated
signaling.

The exact size of the GPCR superfamily is unknown, but

nearly 800 dierent human genes (or 4% of the entire protein-coding genome) have been predicted from
genome sequence analysis.[8] Although numerous classication schemes have been proposed, the superfamily was
classically divided into three main classes (A, B, and C)
with no detectable shared sequence homology between
classes.

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 classied as orphan recepThere are two principal signal transduction pathways in- tors. Despite the lack of sequence homology between
volving the G proteincoupled receptors:
classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin
the cAMP signal pathway and
A group has been further subdivided into 19 subgroups
(A1-A19).[9]
[6]
the phosphatidylinositol signal pathway.
More recently, an alternative classication system
When a ligand binds to the GPCR it causes a conforma- called GRAFS (Glutamate, Rhodopsin, Adhesion,
tional change in the GPCR, which allows it to act as a Frizzled/Taste2, Secretin) has been proposed.[8]
1

3 RECEPTOR STRUCTURE

By this system, GPCRs can be grouped into 6

classes based on sequence homology and functional
similarity:[10][11][12][13]
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)

6. 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
7. Cell density sensing: A novel GPCR role in regulating cell density sensing.
8. Homeostasis modulation (e.g., water balance).[19]
9. Involved in growth and metastasis of some types of
tumors.[20]

The human genome encodes thousands of G proteincoupled receptors,[14] about 350 of which detect hor3 Receptor structure
mones, growth factors, and other endogenous ligands.
Approximately 150 of the GPCRs found in the human
GPCRs are integral membrane proteins that possess
genome have unknown functions.
seven membrane-spanning domains or transmembrane
Some web-servers[15] and bioinformatics prediction helices.[21][22] The extracellular parts of the receptor can
methods[16][17] have been used for predicting the classi- be glycosylated. These extracellular loops also contain
cation of GPCRs according to their amino acid sequence two highly conserved cysteine residues that form disulde
alone, by means of the pseudo amino acid composition bonds to stabilize the receptor structure. Some sevenapproach.
transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their
protein.

Physiological roles

Similar to GPCRs, the adiponectin receptors 1

and 2 (ADIPOR1 and ADIPOR2) also possess 7
GPCRs are involved in a wide variety of physiological transmembrane domains. However, ADIPOR1 and
processes. Some examples of their physiological roles in- ADIPOR2 are orientated oppositely to GPCRs in the
clude:
membrane (i.e., extracellular N-terminus, cytoplasmic
C-terminus) and do not associate with G proteins.[23]
1. The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation Early structural models for GPCRs were based on their
into cellular signals. Rhodopsin, for example, uses weak analogy to bacteriorhodopsin, for which a structhe conversion of 11-cis-retinal to all-trans-retinal ture had been determined by both electron diraction
(PDB 2BRD, 1AT9)[24][25] and X ray-based crystalfor this purpose
lography (1AP9).[26] In 2000, the rst crystal struc2. The gustatory sense (taste): GPCRs in taste cells ture of a mammalian GPCR, that of bovine rhodopsin
mediate release of gustducin in response to bitter- (1F88), was solved.[27] While the main feature, the sevenand sweet-tasting substances.
transmembrane helices, is conserved, the relative orien3. The sense of smell: Receptors of the olfactory tation of the helices dier signicantly from that of bacstructure of a human
epithelium bind odorants (olfactory receptors) and teriorhodopsin. In 2007, the rst [28]
GPCR
was
solved
(2R4R,
2R4S).
This was followed
pheromones (vomeronasal receptors)
immediately by a higher resolution structure of the same
4. Behavioral and mood regulation:
Receptors receptor (2RH1).[29][30] This human 2 -adrenergic recepin the mammalian brain bind several dierent tor GPCR structure, proved highly similar to the bovine
neurotransmitters, including serotonin, dopamine, rhodopsin in terms of the relative orientation of the sevenGABA, and glutamate
transmembrane helices. However, the conformation of
5. Regulation of immune system activity and the second extracellular loop is entirely dierent between
inammation: Chemokine receptors bind ligands the two structures. Since this loop constitutes the lid
that mediate intercellular communication between that covers the top of the ligand binding site, this concells of the immune system; receptors such as formational dierence highlights the diculties in conhistamine receptors bind inammatory mediators structing homology models of other GPCRs based only
and engage target cell types in the inammatory on the rhodopsin structure.
response. GPCRs are also involved in immune- The structures of activated and/or agonist-bound GPCRs
modulation and directly involved in suppression of have also been determined.[31][32][33][34] These structures
indicate how ligand binding at the extracellular side of a
TLR-induced immune responses from T cells.[18]

3
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 G conrmed that the G binds to a cavity created
by this movement.[35]

Structure-function relationships

transduction function (i.e., G-protein coupling). Inverse

agonists and antagonists may also bind to a number of
dierent sites, but the eventual eect 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 ligandbinding. For example, The C-terminus of M3 muscarinic
receptors is sucient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary
for its preassembly with G proteins.[36] In particular,
the C-terminus often contains serine (Ser) or threonine
(Thr) residues that, when phosphorylated, increase the
anity of the intracellular surface for the binding of
scaolding proteins called -arrestins (-arr).[37] Once
bound, -arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellularsignal 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 -arr-mediated G-proteindecoupling and internalization of GPCRs are important
mechanisms of desensitization.[38]

A nal 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 modication of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the eect of
targeting the receptor to cholesterol- and sphingolipidrich microdomains of the plasma membrane called lipid
Two-dimensional schematic of a generic GPCR set in a Lipid rafts. As many of the downstream transducer and efRaft. Click the image for higher resolution to see details regarding fector molecules of GPCRs (including those involved in
the locations of important structures.
negative feedback pathways) are also targeted to lipid
rafts, this has the eect of facilitating rapid receptor sigIn terms of structure, GPCRs are characterized by an ex- naling.
tracellular N-terminus, followed by seven transmembrane
(7-TM) -helices (TM-1 to TM-7) connected by three GPCRs respond to extracellular signals mediated by
intracellular (IL-1 to IL-3) and three extracellular loops a huge diversity of agonists, ranging from proteins to
(EL-1 to EL-3), and nally an intracellular C-terminus. biogenic amines to protons, but all transduce this signal
The GPCR arranges itself into a tertiary structure re- via a mechanism of G-protein coupling. This is made
sembling a barrel, with the seven transmembrane helices possible by a guanine-nucleotide exchange factor (GEF)
forming a cavity within the plasma membrane that serves domain primarily formed by a combination of IL-2 and
a ligand-binding domain that is often covered by EL- IL-3 along with adjacent residues of the associated TM
2. Ligands may also bind elsewhere, however, as is the helices.
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 5 Mechanism
also contains a ligand-binding domain. Upon glutamatebinding to an mGluR, the N-terminal tail undergoes a
conformational change that leads to its interaction with The G protein-coupled receptor is activated by an exterthe residues of the extracellular loops and TM domains. nal signal in the form of a ligand or other signal mediaThe eventual eect of all three types of agonist-induced tor. This creates a conformational change in the receptor,
activation is a change in the relative orientations of the causing activation of a G protein. Further eect depends
TM helices (likened to a twisting motion) leading to a on the type of G protein. G proteins are subsequently inwider intracellular surface and revelation of residues of activated by GTPase activating proteins, known as RGS
the intracellular helices and TM domains crucial to signal proteins.

MECHANISM

5.2 Conformational change

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.[39]

5.1

Ligand binding

GPCRs include: receptors for sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, 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
eect), glucagon, acetylcholine (muscarinic eect), and
serotonin); chemokines; lipid mediators of inammation
(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 identied 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.[40]

Crystal structure of activated beta-2 adrenergic receptor in complex with Gs(PDB entry 3SN6). The receptor is colored red, G
green, G cyan, and G yellow. The C-terminus of G 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 conformation change in the
receptor that is transmitted to the bound G subunit of
the heterotrimeric G protein. The activated G subunit
exchanges GTP in place of GDP which in turn triggers
the dissociation of G subunit from the G dimer and
from the receptor. The dissociated G and G 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 transduction.[41]
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states.[42] The binding of ligands to the receptor may shift the equilibrium toward the active receptor
states.[43] 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 aect the equilibrium. It is not yet known
how exactly the active and inactive states dier from each
other.

5.4

5.3

Crosstalk

G-protein activation/deactivation cycle 5.4 Crosstalk

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 -subunit of a heterotrimeric
G-protein. These G-proteins are a trimer of , , and
subunits (known as G, G, and G, 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-proteins -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 G-GTP
monomer and a tightly interacting G dimer, which are
now free to modulate the activity of other intracellular
proteins. The extent to which they may diuse, however, is limited due to the palmitoylation of G and the
presence of an isoprenoid moiety that has been covalently
added to the C-termini of G.

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.[44] Integrin signaling will phosphorylate FAK, which can then
decrease GPCR Gs activity.

6 GPCR signaling
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.[36] For example,
binding of G proteins to receptors aects the receptors
anity 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 G . Adenylate cyclase activity is
Because G also has slow GTPGDP hydrolysis capa- activated when it binds to a subunit of the activated G
bility, the inactive form of the -subunit (G-GDP) is protein. Activation of adenylate cyclase ends when the G
eventually regenerated, thus allowing reassociation with protein returns to the GDP-bound state.
a G dimer to form the resting G-protein, which can
again bind to a GPCR and await activation. The rate Adenylate cyclases (of which 9 membrane-bound and one
of GTP hydrolysis is often accelerated due to the ac- cytosolic forms are known in humans) may also be actitions of another family of allosteric modulating proteins vated or inhibited in other ways (e.g., Ca2+/Calmodulin
called Regulators of G-protein Signaling, or RGS pro- binding), which can modify the activity of these enzymes
teins, which are a type of GTPase-Activating Protein, or in an additive or synergistic fashion along with the G proGAP. In fact, many of the primary eector proteins (e.g., teins.
adenylate cyclases) that become activated/inactivated The signaling pathways activated through a GPCR are
upon interaction with G-GTP also have GAP activity. limited by the primary sequence and tertiary structure of
Thus, even at this early stage in the process, GPCR- the GPCR itself but ultimately determined by the parinitiated signaling has the capacity for self-termination.
ticular conformation stabilized by a particular ligand, as

GPCR SIGNALING

gard to signaling properties, but in general they appear

reasonably grouped into four classes. Because the signal
transducing properties of the various possible combinations do not appear to radically dier from one another,
these classes are dened according to the isoform of their
-subunit.[7]:1163
While most GPCRs are capable of activating more than
one G-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 agonistdirected tracking, or conformation-specic agonism).
However, the binding of any single particular agonist may
also initiate activation of multiple dierent G-proteins,
as it may be capable of stabilizing more than one conformation of the GPCRs GEF domain, even over the
course of a single interaction. In addition, a conformation that preferably activates one isoform of G may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modications (e.g., phosphorylation) that alter the G-protein
preference. Regardless of these various nuances, the
GPCRs preferred coupling partner is usually dened according to the G-protein most obviously activated by
the endogenous ligand under most physiological and/or
experimental conditions.
6.1.1 G signaling

G-protein-coupled receptor mechanism

well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types
of transducers: G-proteins and -arrestins. Because arrs have high anity 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.

6.1

G-protein-dependent signaling

There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (G ,
G/, G /, and G/). Each sub-class of G-protein
consists of multiple proteins, each the product of multiple genes and/or splice variations that may imbue them
with dierences ranging from subtle to distinct with re-

1. The eector of both the G and G/ pathways

is the cyclic-adenosine monophosphate (cAMP)generating enzyme adenylate cyclase, or AC. While
there are ten dierent AC gene products in mammals, each with subtle dierences in tissue distribution and/or function, all catalyze the conversion of
cytosolic adenosine triphosphate (ATP) to cAMP,
and all are directly stimulated by G-proteins of the
G class. In contrast, however, interaction with G
subunits of the G/ type inhibits AC from generating cAMP. Thus, a GPCR coupled to G counteracts the actions of a GPCR coupled to G/, 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-specic protein kinase A
(PKA) family. Thus cAMP is considered a second
messenger and PKA a secondary eector.
2. The eector of the G / pathway is phospholipase
C- (PLC), which catalyzes the cleavage
of membrane-bound phosphatidylinositol 4,5biphosphate (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 elicit Ca2+ release from the ER, while
DAG diuses along the plasma membrane where
it may activate any membrane localized forms of
a second ser/thr kinase called protein kinase C

7
(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 eector. 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).

ter 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 o.
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 eect
of bradykinin.[46]

3. The eectors of the G/ pathway are three

RhoGEFs (p115-RhoGEF, PDZ-RhoGEF, and
LARG), which, when bound to G/ 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 G/ also couple to other sub-classes, often
6.2.2 GPCR-independent signaling
G /.
erotrimeric G-proteins
6.1.2

G signaling

The above descriptions ignore the eects of G

signalling, which can also be important, in particular in
the case of activated G/-coupled GPCRs. The primary eectors of G 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 (PI3K) isoforms.

6.2

G-protein-independent signaling

Although they are classically thought of working

only together, GPCRs may signal through G-proteinindependent mechanisms, and heterotrimeric 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 -arrs, GRKs, and Srcs. In addition, further scaolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins)
may also act as signal transducers. Most often the eector is a member of the MAPK family.
6.2.1

by

het-

Although it is a relatively immature area of research, it

appears that heterotrimeric G-proteins may also take part
in non-GPCR signaling. There is evidence for roles as
signal transducers in nearly all other types of receptormediated 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 specic 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
G vs. G subunits to these processes are still unclear.

7 Details of cAMP and PIP2 pathways

Examples

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 Activation eects of cAMP on protein kinase A
slime mold D. discoideum despite the absence of the associated G protein - and -subunits.[45]
There are two principal signal transduction pathways inIn mammalian cells, the much-studied 2 -adrenoceptor volving the G protein-linked receptors: the cAMP signal
has been demonstrated to activate the ERK2 pathway af- pathway and the phosphatidylinositol signal pathway.[6]

RECEPTOR REGULATION

ger in cellular metabolism and is an allosteric activator of

protein kinase A.

The eect of Rs and Gs in cAMP signal pathway

Protein kinase A is an important enzyme in cell

metabolism due to its ability to regulate cell metabolism
by phosphorylating specic committed enzymes in the
metabolic pathway. It can also regulate specic 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 biological eects.
These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to
5'-AMP and inactivates protein kinase A.

7.2 Phosphatidylinositol signal pathway

Main article: IP3/DAG pathway

The eect of Ri and Gi in cAMP signal pathway

7.1

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.

In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor
(G ) 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 eects 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 anity 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.

Stimulative regulative G-protein is a G-protein linked

to stimulative hormone receptor (Rs), and its subunit
upon activation could stimulate the activity of an enzyme
or other intracellular metabolism. On the contrary, in- 8 Receptor regulation
hibitory regulative G-protein is linked to an inhibitory
hormone receptor, and its subunit upon activation could GPCRs become desensitized when exposed to their liginhibit the activity of an enzyme or other intracellular and for a prolonged period of time. There are two recogmetabolism.
nized forms of desensitization: 1) homologous desensiAdenylyl cyclase is a 12-transmembrane glycoprotein that tization, in which the activated GPCR is downregulated;
catalyzes ATP to form cAMP with the help of cofactor and 2) heterologous desensitization, wherein the activated
Mg2+ or Mn2+ . The cAMP produced is a second messen- GPCR causes downregulation of a dierent GPCR. The

8.3

Mechanisms of GPCR signal termination

key reaction of this downregulation is the phosphorylation

of the intracellular (or cytoplasmic) receptor domain by
protein kinases.

8.1

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 2 -adrenoceptors, this phosphorylation results
in the switching of the coupling from the G class of Gprotein to the G class.[47] cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.[48]

8.2

Phosphorylation by GRKs

9
In many cases, arrestins binding to the receptor
is a prerequisite for translocation. For example,
beta-arrestin bound to 2 -adrenoreceptors acts as an
adaptor for binding with clathrin, and with the betasubunit of AP2 (clathrin adaptor molecules); thus,
the arrestin here acts as a scaold assembling the
components needed for clathrin-mediated endocytosis of 2 -adrenoreceptors.[51][52]

8.3 Mechanisms of GPCR signal termination

As mentioned above, G-proteins may terminate their own
activation due to their intrinsic GTPGDP 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 G
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 diuse 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.

The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. Gprotein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling.
They constitute a family of seven mammalian serinethreonine protein kinases that phosphorylate agonistbound 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
In addition, the GPCR may be desensitized itself. This
proteins and calcium-sensitive proteins.[49]
can occur as:
Phosphorylation of the receptor can have two consequences:
1. a direct result of ligand occupation, wherein the
change in conformation allows recruitment of
1. Translocation: The receptor is, along with the part
GPCR-Regulating Kinases (GRKs), which go on to
of the membrane it is embedded in, brought to
phosphorylate various serine/threonine residues of
the inside of the cell, where it is dephosphorylated
IL-3 and the C-terminal tail. Upon GRK phoswithin the acidic vesicular environment[50] and then
phorylation, the GPCRs anity for -arrestin (brought back. This mechanism is used to reguarrestin-1/2 in most tissues) is increased, at which
late long-term exposure, for example, to a hormone,
point -arrestin may bind and act to both sterically
by allowing resensitisation to follow desensitisahinder G-protein coupling as well as initiate the
tion. Alternatively, the receptor may undergo lysoprocess of receptor internalization through clathrinzomal degradation, or remain internalised, where it
mediated endocytosis. Because only the liganded reis thought to participate in the initiation of signalling
ceptor is desensitized by this mechanism, it is called
events, the nature of which depending on the interhomologous desensitization
nalised vesicles subcellular localisation.[48]
2. the anity for -arrestin may be increased in a
2. Arrestin linking: The phosphorylated receptor can
ligand occupation and GRK-independent manner
be linked to arrestin molecules that prevent it from
through phosphorylation of dierent ser/thr sites
binding (and activating) G proteins, in eect switch(but also of IL-3 and the C-terminal tail) by PKC
ing it o for a short period of time. This mechaand PKA. These phosphorylations are often sunism is used, for example, with rhodopsin in retina
cient to impair G-protein coupling on their own as
cells to compensate for exposure to bright light.
well.

10
3. PKC/PKA may, instead, phosphorylate GRKs,
which can also lead to GPCR phosphorylation and
-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 -arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaolding
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 o, 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 tracked back to the plasma membrane or
targeted to lysosomes for degradation.

11

DICTYOSTELIUM DISCOIDEUM

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.

9 Receptor oligomerization
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[53] of functional
receptors.[54]

At any point in this process, the -arrestins may also recruit other proteinssuch as the non-receptor tyrosine
kinase (nRTK), c-SRCwhich 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 10 Origin and diversication of the
to one another. Another target of c-SRC are the dynamin
superfamily
molecules involved in endocytosis. Dynamins polymerize
around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for Signal transduction mediated by the superfamily of
the conformational change allowing the nal pinching GPCRs dates back to the origin of multicellularity.
o from the membrane.
Mammalian-like GPCRs are found in fungi, and have
been classied according to the GRAFS classication
system based on GPCR ngerprints.[55] Identication
8.4 GPCR cellular regulation
of the superfamily members across the eukaryotic domain, and comparison of the family-specic motifs, have
Receptor desensitization is mediated through a combinashown that the superfamily of GPCRs have a common
tion phosphorylation, -arr binding, and endocytosis as
origin.[56] Characteristic motifs indicate that three of the
described above. Downregulation occurs when endocyve GRAFS families, Rhodopsin, Adhesion, and Frizzled,
tosed receptor is embedded in an endosome that is trafevolved from the Dictyostelium discoideum cAMP recepcked to merge with an organelle called a lysosome. Betors before the split of Opisthokonts. Later, the Secretin
cause lysosomal membranes are rich in proton pumps,
family evolved from the Adhesion GPCR receptor family
their interiors have low pH (4.8 vs. the pH7.2 cybefore the split of nematodes.
tosol), 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
11 Dictyostelium discoideum
together may be cleaved. Whether or not a given receptor is tracked to a lysosome, detained in endosomes, or
tracked back to the plasma membrane depends on a va- A novel GPCR containing a lipid kinase domain has reriety of factors, including receptor type and magnitude of cently been identied in Dictyostelium discoideum that
the signal. GPCR regulation is additionally mediated by regulates cell density sensing.[57]

11

12

See also

G protein-coupled receptors database

Metabotropic receptor
Orphan receptor
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

13

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14 External links
G-protein-coupled receptors at the US National
Library of Medicine Medical Subject Headings
(MeSH)
Wikipedia:MeSH
D12.776#MeSH
D12.776.543.750.100 --- receptors.2C g-proteincoupled
GPCR Database. IUPHAR Database. International Union of Basic and Clinical Pharmacology.
Retrieved 2008-08-11.
Vriend G, Horn F (2006-06-29). GPCRDB: Information system for G protein-coupled receptors
(GPCRs)". Molecular Class-Specic Information
System (MCSIS) project. Retrieved 2008-08-11.
G Protein-Coupled Receptors on the NET. Retrieved 2010-11-10. a classication of GPCRs
PSI GPCR Network Center. Retrieved 2013-0711. a Protein Structure Initiative:Biology Network
Center aimed at determining the 3D structures of
representative GPCR family proteins
GLASS: A comprehensive database for
experimentally-validated GPCR-ligand associations

15 Further reading
The Nobel Prize in Chemistry 2012. Retrieved
2012-10-10.

14
A phylogenetic tree of all human GPCRs. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis
JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR,
Wright AC, Bergmann JE, Gaitanaris GA (2003).
The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA 100
(8): 49038. doi:10.1073/pnas.0230374100. PMC
153653. PMID 12679517.. Retrieved 2008-08-11.
GPCR Reference Library. Retrieved 2008-08-11.
Reference for molecular and mathematical models
for the initial receptor response
GPCR structures in the PDB

15 FURTHER READING

15

16
16.1

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Miguel Andrade, OrphanBot, Roadnottaken, PetWolverine, Stuckinkiel, James McNally, Drphilharmonic, Ligulembot, KJS77, Shrimp
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Darkspace08, Brainiacal, Monkbot, Immunowiz, Neokit and Anonymous: 168

16.2

Images

File:7TM4_(GPCR).png Source: http://upload.wikimedia.org/wikipedia/commons/6/60/7TM4_%28GPCR%29.png License: Public domain Contributors: Transferred from en.wikipedia; transfer was stated to be made by User:valeryns. Original artist: Original uploader was
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File:Beta2Receptor-with-Gs.png Source: http://upload.wikimedia.org/wikipedia/commons/4/46/Beta2Receptor-with-Gs.png License:
Public domain Contributors: From PDB entry 3SN6.
Original artist: Nakane
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artist: ?
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3.0 Contributors: Own work Original artist: Repapetilto
File:GPCR_and_itegrin_signaling_diagram.png Source: http://upload.wikimedia.org/wikipedia/commons/3/34/GPCR_and_itegrin_
signaling_diagram.png License: Public domain Contributors: The Journal of Allergy Original artist: Thai Tran Lab
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File:The_effect_of_Ri_and_Gi_in_cAMP_signal_pathway.jpg Source: http://upload.wikimedia.org/wikipedia/commons/a/a3/The_
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16.3

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