GPCRs are the largest and most diverse group of integral membrane proteins. These proteins are used by cells to convert extracellular signals into intracellular responses and mediate most of our physiological responses to hormones, neurotransmitters as well as responses to vision, olfaction and taste signal. They mediate most of our and environmental stimulants, and so have a great potential as therapeutic targets for a broad spectrum of diseases. At the most basic level, all GPCRS are characterized by the presence of seven membrane-spanning alpha helical segments separated by alternating intracellular and extracellular loop regions. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times.

1. G-protein-
coupled-receptors
(GPCRs)
-Submitted by
Rhea Ann Expidite

2. Introduction
● GPCRs are the largest and most diverse group of integral membrane proteins.
● These proteins are used by cells to convert extracellular signals into intracellular responses and mediate
most of our physiological responses to hormones, neurotransmitters as well as responses to vision,
olfaction and taste signal.
● They mediate most of our and environmental stimulants, and so have a great potential as therapeutic
targets for a broad spectrum of diseases.
● At the most basic level, all GPCRS are characterized by the presence of seven membrane-spanning
alpha helical segments separated by alternating intracellular and extracellular loop regions.
● Coupling with G proteins, they are called seven transmembrane receptors because they pass through
the cell membrane seven times.
● There are more than 800 GPCR family members, with the vast majority being olfactory receptors.
● The first GPCR was Rhodopsin and its crystal structure was discovered in 2000.

3. Structure
● A GPCR is basically composed of three parts: the extracellular region, the TM region, and the intracellular
region.
-the extracellular region contains N terminus and three extracellular loops (ECL1–ECL3);
-the TM region contains seven TM α-helices (TM1–TM7);
-the intracellular region contains three intracellular loops (ICL1–ICL3) and an intracellular amphipathic
short α-helix (H8) lying perpendicular to the membrane plane, and the C terminus.
● Beginning at the N-terminus, this long protein winds up and down through the cell membrane, with the long
middle segment traversing the membrane seven times in a serpentine pattern.
● The last of the seven domains is connected to the C-terminus.

4. What Do GPCRs Do?
● As their name implies, GPCRs interact with G proteins in the plasma membrane. When an external
signaling molecule binds to a GPCR, it causes a conformational change in the GPCR.
● This change then triggers the interaction between the GPCR and a nearby G protein.
● G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate
(GTP) and guanosine diphosphate (GDP).
● The G proteins that associate with GPCRs are heterotrimeric, meaning they have three different
subunits: an alpha subunit, a beta subunit, and a gamma subunit.
● Two of these subunits — alpha and gamma — are attached to the plasma membrane by lipid
anchors.

5. ● A G protein alpha subunit binds either GTP or
GDP depending on whether the protein is active
(GTP) or inactive (GDP).
● In unstimulated cells, the state of G alpha
(orange circles) is defined by its interaction
with GDP, G beta-gamma (purple circles), and
a G-protein-coupled receptor (GPCR; light
green loops).
● Upon receptor stimulation by a ligand called an agonist, the state of the receptor changes.
● G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to
G alpha activation. G alpha then goes on to activate other molecules in the cell.
● G proteins remain active as long as their alpha subunits are joined with GTP.
● However, when this GTP is hydrolyzed back to GDP, the subunits once again assume the form of an inactive
heterotrimer, and the entire G protein reassociates with the now-inactive GPCR.
● In this way, G proteins work like a switch — turned on or off by signal-receptor interactions on the cell's surface.
● Whenever a G protein is active, both its GTP-bound alpha subunit and its beta-gamma dimer can relay messages in
the cell by interacting with other membrane proteins involved in signal transduction.
● Some G proteins stimulate the activity of these targets, whereas others are inhibitory.

6. ● In this diagram of G-protein-coupled receptor activation, the
alpha, beta, and gamma subunits are shown with distinct
relationships to the plasma membrane.
● After exchange of GDP with GTP on the alpha subunit, both the
alpha subunit and the beta-gamma complex may interact with
other molecules to promote signaling cascades.
● Both the alpha subunit and the beta-gamma complex remain
tethered to the plasma membrane while they are activated.
● These activated subunits can act on ion channels in the cell
membrane, as well as cellular enzymes and second messenger
molecules that travel around the cell.
Figure : The relationships of G proteins
to the plasma membrane

7. What Second Messengers Do GPCR Signals Trigger in Cells?
● Activation of a single G protein can affect the production of hundreds or even thousands of second messenger
molecules.
● One especially common target of activated G proteins is adenylyl cyclase, a membrane-associated enzyme
that, when activated by the GTP-bound alpha subunit, catalyzes synthesis of the second messenger cAMP
from molecules of ATP.
● In humans, cAMP is involved in responses to sensory input, hormones, and nerve transmission, among others.
● Phospholipase C is another common target of activated G proteins. This membrane-associated enzyme
catalyzes the synthesis of not one, but two second messengers — DAG and IP3 — from the membrane lipid
phosphatidyl inositol.
● This particular pathway is critical to a wide variety of human bodily processes. For instance, thrombin
receptors in platelets use this pathway to promote blood clotting.

8. ● Binding of an agonist to the seven-transmembrane G-protein-
coupled receptor in the plasma membrane activates a pathway
that involves G proteins as well as cAMP-related pathways that
modulate cellular signaling.
● In this example, the activated G alpha (Gαi/0) proteins inhibit (-)
adenylyl cyclase (AC, on the right), the enzyme that induces
formation of cAMP, which in turn results in the activation of
protein kinase A (PKA).
● This in turn activates a molecule called cAMP-responsive
element-binding protein (CREB), which modulates gene
transcription.
● The activated G alpha proteins can also have a variety of other
effects. These effects include activating the mitogen-activated
protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)
pathways.
● Activation of the enzyme phospholipase A2 (PLA2) may also
occur, which induces the release of arachidonic acid (AA), as
well as inhibition of the Na+/H+ exchanger in the plasma
membrane, and the lowering of intracellular Ca2+ levels (exact
mechanism unknown, ?).
● Subsequent activation of the MAPK and PI3K pathways results
in the phosphorylation of extracellular signal-regulated kinases
(ERKs) and protein kinase B (PKB), respectively.
● Activated PKB will subsequently phosphorylate and thereby
inhibit the action of glycogen synthase kinase 3beta (GSK3beta),
a major kinase in the brain.
Figure: Signaling cascades within a cell can interact to affect multiple
molecules in the cell, leading to secretion of substances from the cell,
ion channel opening, and transcription.

10. Rhodopsin Like Receptor family
● RLR represent the predominant class of GPCRs and contain highly
conserved amino acids.
● It has a disulphide bridge between first and second extracellular
loops (ECLs), palmitoylated cys in C-tail.
● Rhodopsin is the rod cell specific visual pigment protein found in
the vertebrate retina.
● G-protein-coupled receptors, GPCRs, constitute a vast protein
family that encompasses a wide range of functions (including
various autocrine, paracrine, and endocrine processes).
● The rhodopsin-like GPCRs themselves represent a widespread
protein family that includes hormone, neuropeptide,
neurotransmitter, and light receptors, all of which transduce
extracellular signals through interaction with guanine nucleotide-
binding (G) proteins.
● Mutations cause disorders like Retinitis pigmentosa and congenital
night blindness.
Structure of rhodopsin: A G protein-coupled
receptor.

11. Secretin receptor family
● The secretin-receptor family of GPCRs include vasoactive intestinal
peptide receptors and receptors for secretin, calcitonin and parathyroid
hormone/parathyroid hormone-related peptides.
● These receptors activate adenylyl cyclase and the phosphatidyl-
inositol-calcium pathway.
● The receptors in this family have 7 transmembrane helices like
rhodopsin-like GPCRs.
● However, there is no significant sequence identity between these two
GPCR families and the secretin-receptor family has its own
characteristic 7TM signature.
● They have a presumed non-hormonal function and thus, they are more
commonly referred to as Adhesion G protein-coupled receptors,
making the Adhesion subfamily the more basal group.
Human secretin receptor Gs
complex

12. Metabotropic glutamate receptor
● The metabotropic glutamate receptors, or mGluRs, are a type of glutamate
receptor that are active through an indirect metabotropic process. They are
members of the group C family of G-protein-coupled receptors, or GPCRs.
● Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that
functions as an excitatory neurotransmitter.
● The mGluRs perform a variety of functions in the central and peripheral
nervous systems: For example, they are involved in learning, memory,
anxiety, and the perception of pain.
● They are found in pre- and postsynaptic neurons in synapses of the
hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the
brain and in peripheral tissues.
● Unlike ionotropic receptors, metabotropic glutamate receptors are not ion
channels. Instead, they activate biochemical cascades, leading to the
modification of other proteins, such as ion channels.
● This can lead to changes in the synapse's excitability, for example by
presynaptic inhibition of neurotransmission or modulation and even induction
of postsynaptic responses.
Metabotropic Glutamate
Receptor 5 Apo Form

13. Adhesion Receptors
● Adhesion GPCRs are a class of 33 human protein receptors with a broad distribution
in embryonic and larcal cells, cells of the reproductive tract, neurons, leukocytes and
a variety of tumors.
● Adhesion G protein-coupled receptors (aGPCRs) — one of the five main families in
the GPCR superfamily — have several atypical characteristics, including large, multi-
domain N termini and a highly conserved region that can be autoproteolytically
cleaved.
● The extracellular region of adhesion GPCRs can be exceptionally long and contain a
variety of structural domains that are known for the ability to facilitate cell and
matrix interactions.
● Studies on inherited mutations in humans, have provided striking evidence regarding
the physiological importance of various adhesion GPCRs.
● For example, mutations to GPR56 have been shown to cause the inherited human
developmental disorder known as bilateral frontal parietal polymicrogyria, which is
characterized by a malformed cerebral cortex due to the overmigration of neuronal
progenitors

14. Frizzled
● Frizzled is a family of atypical G protein-coupled receptors that serve
as receptors in the Wnt signaling pathway and other signaling pathway.
● When activated, Frizzled leads to activation of Dishevelled in the
cytosol.
● Frizzled proteins also play key roles in governing cell polarity,
embryonic development, formation of neural synapses, cell
proliferation, and many other processes in developing and adult
organisms.
● These processes occur as a result of one of three signaling pathways.
These include the canonical Wnt/β-catenin pathway, Wnt/calcium
pathway, and planar cell polarity (PCP) pathway.
● Mutations in the human frizzled-4 receptor have been linked to familial
exudative vitreoretinopathy, a rare disease affecting the retina at the
back of the eye, and the vitreous, the clear fluid inside the eye.

15. Conclusion
● Nearly 40% of the drugs approved for marketing by the FDA target GPCRs.
● 800-1,000 different GPCRs and the drugs that are marketed target less than 50 GPCRs.
● GPCR will continue to be highly important in clinical medicine because of their large number, wide
expression and role in physiologically important responses.
● Future discoveries will reveal new GPCR drugs, in part because it is relatively easy to screen for
pharmacologic agents that access these receptors and stimulate or block receptor-mediated biochemical
or physiological responses.

16. Thank You