G PROTEIN COUPLED

RECEPTORS

G- PROTEIN COUPLED RECEPTORS

(GPCR)
Also known as METABOTROPIC RECEPTOR
or 7-TRANSMEMBRANE-SPANNING
(HEPTAHELICAL) RECEPTORS.
Membrane receptor coupled to extracellular
effector system via G-Protein.
Largest known receptor family more than
1000
Constitutes > 3% of the human genome.
Comprises receptors for a diverse array of
molecules: neurotransmitters, odorants, lipids,
neuropeptides, large glycoprotein hormones.

G- PROTEIN COUPLED RECEPTORS

(GPCR)
Examples of GPCRs:
Muscarinic acetylcholine receptor
(several types)
Catecholamine receptors
Histamine receptors (H11, H22)
5-HT receptors other than 5-HT33

GABABB receptors
Metabotropic glutamate receptors
Peptide receptors (Endorphin,
cholecystokinin..)

MOLECULAR STRUCTURE
Single polypeptide
chain of up to
1100 residues
SEVEN
transmembrane
helices;
extracellular Nterminal and
intracellular Cterminal domain.
3 intracellular
loops and 3
extracellular loops

MOLECULAR STRUCTURE-THREE
FAMILIES

1.
1. RHODOPSIN
RHODOPSIN
FAMILY
FAMILY

2.
2. SECRETIN/
SECRETIN/ GLUCAGON
GLUCAGON
RECEPTOR
RECEPTOR FAMILY
FAMILY

3.
3.
METABOTROPHIC
METABOTROPHIC
GLUTAMATE
GLUTAMATE
RECEPTOR/
RECEPTOR/
CALCIUM
CALCIUM SENSOR
SENSOR
FAMILY
FAMILY

MOLECULAR STRUCTURE-THREE
FAMILIES
FAMILY

RECEPTORS

STRUCTURAL
FEATURES

RHODOSPIN

Largest group
Amines, NTs,
Neuropeptides,
Cannabinoids

Short
extracellular tail
Ligand binding
sites: helices
(amines) and
extracellular
loops (peptides)

SECRETIN/GLUCAGO
N RECEPTOR FAMILY

Receptor for
peptide hormones
like secretin,
glucagon,
calcitonin

Intermediate
extracellular tail
incorporating
ligand binding
site

METABOTROPHIC
Small group
GLUTAMATE
Glutamate,
RECEPTOR/ CALCIUM
GABAB, Ca+2
SENSOR FAMILY
sensing receptors

Long extracellular
tail incorporating
ligand binding
site

RECEPTOR ACTIVATION
Binding of agonist molecules
Rhodospin has its own inbuilt agonist
molecule, retinal, which isomerizes from
trans (inactive) to cis (active) form when it
absorbs photon.
Protease- activated receptors (PARs) :
Proteases like thrombin, activates PARs by
snipping off the end of the extracellular Nterminal tail. The exposed N- terminal
reside then bind to receptor domains in the
extracellular loops, functioning as tethered
agonist.

RECEPTOR ACTIVATION

G- PROTEINS AND THEIR ROLE

G- proteins comprise a family of
membrane resident protein whose
function is to recognize activated
GPCRs and pass message to the
effector systems that generate a
cellular response.
Go-between proteins
Interaction with guanine nucleotides,
GTP and GDP so called G-Protein.

G- PROTEINS AND THEIR ROLE

G- proteins consists of three subunits: , and .
Guanine molecules binds to subunit, which has
enzymatic activity, catalyzing GTP to GDP.
and , remains together and form complex.
All three subunits are anchored to the membrane
through fatty acid chin, coupled to G protein
through a reaction called prenylation.
They are freely diffusible in membrane, so single
pool of G- protein can interact with several
different receptors and effectors.
20 subtypes of , 6 subtypes of and 12
subtypes of

G- PROTEINS AND THEIR ROLE

G- PROTEINS AND THEIR ROLE

TARGETS FOR G- PROTEINS

1. Adenylyl cyclase, the enzyme
responsible for cAMP formation
2. Phospholipase C, the enzyme
responsible for inositol phosphate and
diacylglycerol (DAG) formation.
3. Ion channels, particularly potassium and
calcium.
4. Rho a/ Rho kinase, a system that
controls the activity of many signaling
pathways controlling cell growth and
proliferation, smooth muscle contraction
etc.

TARGETS FOR G- PROTEINS-Adenylyl

cyclase
cAMP is a nucleotide synthesized from ATP by
membrane bound enzyme adenylyl cyclase.
Produced continuously and inactivated by
phosphodiesterases (PDEs) to 5- AMP.
cAMP regulates many aspects of cellular function
including, for example, enzyme involved in energy
metabolism, cell division and cell differentiation,
ion transport, ion channels, and the contractile
proteins in smooth muscle.
cAMP activates protein kinases for all these
functions.
Protein kinases regulate the function by controlling
phosphorylation.
Examples: - adrenoreceptor activation for fat

TARGETS FOR G- PROTEINS-Phospholipase C/

inositol phosphate system
PIP22 is substrate for enzyme phospholipase C (PCL )
PCL is activated by various agonists mediated by Gprotein.
PCL splits PIP22 to DAG (Diacylglycerol) and IP33 (Inositol
triphosphate).
IP33 acts on specific receptor (IP33 receptor), which is
ligand gated calcium channel present on membrane of
ER; thus control release of intracellular calcium.
IP33 is converted to IP44 by protein kinases which might
also increases calcium release.
DAG activates PKC, which catalyzes phosphorylation of
a variety of intracellular protein.
IP33 is inactivated by dephosphorylation of inositol and
DAG is converted to phosphatidic acid and these two

TARGETS FOR G- PROTEINS- Ion

channels
Function directly on ion channels
without involvement of secondary
messenger.
Examples: mAChRs are known to
enhance K++ permeability (thus
polarizing the cells and inhibiting
electrical activity); Opiate analgesics
reduce excitability by opening
potassium channels.
These actions are produced by direct

TARGETS FOR G- PROTEINS- Rho-Rho

kinase system
The free G-protein subunit interacts with
guanosine nucleotide exchange factor, which
facilitates GDP-GTP exchange at another GTPase
Rho.
Rho- GDP is activated when GDP-GTP exchange
occurs, which then activates Rho kinase.
Rho kinase phosphorylates many protein and
control wide variety of function like smooth muscle
contraction and proliferation; angiogenesis and
synaptic remodeling.
By enhancing hypoxia induced pulmonary artery
vasoconstriction, activation of Rho kinase is
thought to be important in pathogenesis of
pulmonary hypertension.

DESENSITISATION OF GPCR
Two main processes
1. Receptor phosphorylation
2. Receptor internalization (endocytosis)
The sequence of GPCRs includes
certain residues (serine and
threonine), mainly in C- terminal,
which are phophorylated by kinases
such as PKA, PKC and specific GPCR
kinases (GRKs).

DESENSITISATION OF GPCR
Phosphorylation by PKA and PKC, which are
activated by GPCRs generally leads to impaired
coupling between activated receptor and G-protein,
so agonist effect is reduced. This is non-selective. It
is known as heterologous desensitization. It is
generally weak and short lasting.
Phosphorylation by GRKS are receptor specific,
affects receptor in activated state, so called as
homologous desensitization.
The residues that IGRKs phosphorylates serves as
binding site for arrestins, that blocks interaction
with G- proteins and also target the receptor for
endocyotosis. This is long lasting desensitization.

RECENT DEVELOPMENTS

GPCR dimerisation
Constitutively active
receptors
Agonist specificity
RAMPS and RGS proteins
G-protein independent
signaling

KINASE- LINKED AND RELATED

RECEPTORS

INTRODUCTION
Large and
heterogeneous
group of receptors.
Comprises of
extracellular ligand
binding domain
linked to
intracellular domain
by single
transmembrane
helix.
Example: insulin,
cytokines, growth
factors