2. G Protein-Coupled Receptors
G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain
receptors, 7TM receptors, serpentine receptor, and G protein-linked 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 seven-transmembrane receptors because they pass through the cell
membrane seven times.
The ligands that bind and activate these receptors include:
1. Light sensitive compounds
2. Hormones and
3. Neurotransmitters
That vary in size from small molecules to peptides to large proteins.
3. Families of GPCR
3 Families:
● A – Rhodopsin family
● B - Secretin/Glucagon receptor family eg. Peptide hormones.
● C - Metabotropic Glutamate family eg. GABAB , Glutamate.
4. Rhodopsin Receptor Family
RLR are a family of proteins comprise of G proteincoupled receptors and are
extremely sensitive to light. It activates the G protein transducin (Gt ) to activate
the visual phototransduction pathway. Mutation of the rhodopsin gene is a major
contributor to various retinopathies.
● Remaining receptors are liganded by known Endogenous compounds.
Examples include receptor (FXR) farnesoid X receptor, which is activated by bile
acid, liver X receptor (LXR), and peroxisome proliferatoractivated receptor
(PPAR).
5. 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.
6. Metabotropic Glutamate Family
The metabotropic glutamate receptors (mGluRs) are family C GPCR that
participate in the modulation of synaptic transmission and neuronal excitability
throughout the central nervous system. They have been subdivided into three
groups, based on intracellular signalling mechanisms.
● Group I mGlu receptors (coupled to PLC and intracellular calcium signalling).
● Group II
● Group III receptors are negatively coupled to adenylyl cyclase.
These receptors are generally widely distributed throughout the mammalian brain
with high levels in the cerebellum and thalamus.
7. Structure of G Protein
G proteins, also known as guanine nucleotide-binding proteins, involved in
transmitting signals and function as molecular switches.
Their activity is regulated by factors that control their ability to bind to and
hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When
they bind GTP, they are 'on', and, when they bind GDP, they are 'off '.
● G protein complexes are Made up of alpha (α), beta (β) and gamma (γ)
subunits.
● Beta and gamma subunits can form a stable dimeric complex referred to as
the beta-gamma complex.
8. G proteins located within the cell are activated by GPCRs that span the cell
membrane. Inside the cell, on the plasma membrane, G Protein binds GDP when
inactive and GTP when active. When the GPCRs binds to a signal molecule, the
receptor is activated and changes shape, thereby allowing it to bind to an inactive
G Protein. When this occurs, GTP displaces GDP which activates the G Protein.
9. The newly activated G Protein then migrates along the cell membrane until it binds
to adenylyl cyclase which convert ATP to cAMP that leads to the next step in the
pathway and generates a cellular response. After transduction, G Protein
functions as a GTPase and hydrolyzes the bound GTP which causes a phosphate
group to fall off. This regenerates GDP and inactivates the G Protein and the cycle
repeats.
