G protein-coupled receptor

GPCR
The human beta-2 adrenergic receptor in complex with the partial inverse agonist carazolol[1]
Identifiers
Symbol	7tm_1
Pfam	PF00001
Pfam clan	CL0192
ECOD	5001.1.1
InterPro	IPR000276
PROSITE	PDOC00210
TCDB	9.A.14
OPM superfamily	6
OPM protein	1gzm
CDD	cd14964
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops^[2] (three extracellular loops interacting with ligand molecules, three intracellular loops interacting with G proteins, an N-terminal extracellular region and a C-terminal intracellular region^[2]) of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors.^[3] Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.^[3]

G protein-coupled receptors are found only in eukaryotes, including yeast, and choanoflagellates.^[4] 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 protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors:

• the cAMP signal pathway and
• the phosphatidylinositol signal pathway.^[5]

When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (G_αs, G_αi/o, G_αq/11, G_α12/13).^[6]: 1160

GPCRs are an important drug target and approximately 34%^[7] of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018^[update].^[7] It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.^[3]