G- Protein Coupled Recepters

Shaikh Ameeruddin
Part-II
Roll no. BY3219
 Contents

I. Introduction
II. Structural arrangement of GPCR
III. Classification
IV. GPCR-G protein coupling mechanism
V. GPCRs that activate or inhibit adenylyl cyclase
VI. GPCRs that modulate ion channels
VII.GPCRs that activate phospholipase C
VIII.GPCRs as molecular timers
IX. Conclusion
X. Reference
 Introduction

 G protein coupled receptors are the most numerous class of receptors.

In humans GPCR are used to detect and respond to many different types of signals, including
neurotransmitters , hormones involved in glycogen and fat metabolism, and even photons of light.
Many GPCRs are found primarily in cells of the central nervous system and are used in neuronal
signaling.
GPCRs are of immense medicinal importance, as approximately 30 percent of all drugs used in humans
are agonists or antagonists of specific GPCRs or groups of closely related GPCRs.
 Structural arrangement of GPCR
Many mammalian receptors are coupled to trimeric G-proteins. The G-protein activates an effector
enzyme or channel that generates intracellular second messengers.
All GPCRs comprise of 7 hydrophobic regions that form membrane-spanning alpha helices, connected by
extra cellular and intra cellular loops.
The intra cellular loops form the hetero trimeric G protein binding domains and consist of three sub-units:
i. The alpha sub unit(35kDa)family.
ii. The beta sub unit(35-36kDa)family.
iii. The gamma sub unit(6-10kDa)family.
There is an NH terminus outside of the cell and the COOH terminus inside the cell.
 Classification
 GPCRs’ sequences can be grouped into three distinct families on the
basis of sequence similarity. These are discussed here;
1) Family A: Rhodopsin- like
This family is the largest and includes the receptors for light (rhodopsin)
and adrenaline (adrenergic receptors) and most other 7TM receptor types,
including the olfactory subgroups. The olfactory receptors constitute most of
these sequences, but nearly 200 non-olfactory 7TM receptors that recognize
over 80 distinct ligands have also been functionally characterized.
2) Family B: Secretin-like
Family contains about twenty-five members, including the receptors for the gastrointestinal peptide
hormone family (secretin , glucagon, vasoactive intestinal peptide(VIP)and growth hormone-releasing
hormone),corticotropin-releasing hormone, calcitonin and parathyroid hormone. All family B receptors
are known to couple mainly to active the effector adenylyl cyclase through the G-protein receptor.
3)Family C: Metabotropic glutamate
Family C is a small group and contains the metabotropic glutamate receptor family, the GABA receptor,
and the calcium-sensing receptor , as well as some taste receptors. All family C members have a very
large extracellular amino terminus that seems to be crucial for ligand binding and activation.
 GPCR-G protein coupling Mechanism
All GPCRs have 7 membrane-spanning regions with their N-terminal segment on the
exoplasmic face and their C-terminal segment on the cytosolic face of the plasma membrane .
GPCR-G protein coupling goes through the following steps:
1) The receptor gets activated by the ligand(agonist)
2) G protein binds to the activated receptor.
3) Ligand binding to receptor becomes stronger upon G-protein coupling.
4) GDP is released.
5) G-protein takes up GTP.
6) GTP uptake triggers release of G protein from receptor.
 GPCRs that activate or inhibit adenylyl
cyclase
Two examples of hormones that bind to GPCR are epinephrine(Epi) and nor-epinephrine. Both are
charged compounds that belongs to the catecholamine class. Epi is important in the response to
stress when all tissues require more glucose and fatty acids.
Liberation of glucose and fatty acids is triggered by the binding of Epi to beta-adrenergic receptors
on the surface of hepatic and adipose cells. Epi bound to beta-adrenergic receptors on heart cells
increases contraction rate. Epi bound to beta receptors on smooth muscle cells causes them to relax.
Another type of Epi receptor, the alpha2-adrenergic receptor, is found on other cell types such as
smooth muscle of blood vessels in the intestine, skin and kidneys. When this receptor binds Epi,
blood vessels constrict, cutting off peripheral circulation. Both beta1 and beta2 adrenergic receptors
are coupled to G proteins that activate adenylyl cyclase.
Beta-adrenergic receptors are couples to stimulatory G-proteins(Gs). These G proteins stimulate adenylyl
cyclase to form cAMP from ATP.
The transducing G protein has 3 sub units alpha, beta and gamma.
G-proteins are “on” or activated when GTP is bound and “off” when GDP is bound.
GDP is bound to alpha subunit until ligand binds to receptor . When ligand binds, GDP is exchanged for
GTP.
The GTP alpha subunit dissociates from the beta-gamma(βγ) complex and activates adenylyl cyclase.
The activation is short-lived since GTP is hydrolyzed in seconds.
Once GTP is hydrolyzes, Gα re-associates with beta-gamma.
 GPCR that modulate ion channels
 Several GPCRs activate ion channels either through direct coupling of receptors, G-proteins, and channel or via
a G-protein activating additional second messengers that affect channel activity.
 In muscles, the neurotransmitter acetylcholine binds to receptors that are ligand-gated ion channels. In this case,
the receptor is the channel. Binding of ligand triggers an action potential causing muscle cell to contract.
 In contrast, binding of acetylcholine to receptors in cardiac muscle is inhibitory.
 In cardiac muscle, acetylcholine binds to a GPCR that activates a G-proteins.
 In this case, it is the beta-gamma subunits of the G-protein that binds to and opens a k+ channel.
 The opening of the potassium channel hyperpolarizes the membrane that reduces the frequency of muscle
contraction.
 An example of a GPCR that activates ion channels through additional second messengers is rhodopsin.
Rhodopsin is found in the rod cells of the retina.
 GPCR that activate phospholipase C
 A number of second messengers are derived from phosphatidyl inositol.
 The inositol group extends into the cytosol and can be reversibly
phosphorylated at various positions by the combined action of various
kinases and phosphatases, yielding several different phosphoinositides .
 The amount of PIs in the membrane can be regulated by extracellular
signals.
 Both GPCRs and RTKs stimulate the activity of PI kinases.
 GPCRs as molecular timers
o GPCRs functions as molecular timers.
o The duration of time that GTP remains unhydrolysed is characteristic for
Gα subunits.
o Certain classes of proteins (including some effectors) accelerate Gα’s
intrinsic rate of GTP hydrolysis.
 Conclusion
● As we know cell signaling is a vast topic to be discussed.
● Among the types of receptors GPCR has a high importance and has a great use in signaling
.
● Although plant cells have most of the core elements found in animal G-signaling,
differences in network architecture and intrinsic properties of plant G-protein elements
make G-signaling in plant cells distinct from the animal paradigm.
● In contrast to animal G-proteins, plant G-proteins are self activating.
● The simpler repertoire of G-signal elements in Arabidopsis makes G signaling easier to
manipulate in a multicellular context.
 Reference
Molecular cell biology 2016, lodish , 8th edition.
Molecular biology, S.C. Rastogi .
http://www.ncbi.nlm.nih.gov>pmc
http://en.m.Wikipedia.org>wiki
Thank you