What is G-Protein Coupled Receptor (GPCR) Family?

The G-protein-coupled receptors (GPCRs) are the largest class of cell-surface receptors and are encoded by more than 1,000 genes in the human genome. GPCRs, the primary transmembrane transducers in the nature, are activated by a diverse array of ligands, including hormones, peptides, amino acids, ions and photons of light, carry signals from extracellular ligands to intracellular effectors, and transduce corresponding downstream signals through a wide range of effectors to regulate numerous physiological processes. GPCRs, as the main sensing entities of higher eukaryotes, also confer the ability to see, smell, and taste, and play key roles in endocrine signaling and the regulation of the immune system. GPCRs are expressed ubiquitously and play essential roles of signal transduction in response to a wide variety of extracellular stimuli such as photons, ions, neurotransmitters, hormones and proteins. Given their numerous physiological roles, GPCRs are implicated in numerous diseases and more than 30% of marketed drugs are targeting this receptor family.

Fig 1 Dual role for RGS proteins in GPCR signalling as either inhibitors or effectors

G-Protein Coupled Receptor Family is divided into 3 main classes including Class A (Rhodopsin family)，Class B (Secretin family) and Class C (Orphan GPCR).

--Class A (Rhodopsin family)

Rhodopsin, a prototypical GPCR, plays a crucial role in light perception and has served as a model system for studying GPCR signalling. Rhodopsin and related retinal pigments are members of a family of seven-transmembrane α-helical proteins that contain the chromophore retinal. Light induces isomerization of the retinal ligand to the all-trans-retinal (ATR) configuration, which activates the receptor. The activated rhodopsin is coupled to the G protein transducin (Gt), which is a Gi homologue, to initiate the light-sensing signalling pathways.

Fig 2 Schematic illustration of G-protein-mediated GPCR signalling by the four types of G protein.

Light-activated rhodopsin is specifically coupled to the Gi/o/t subtype

--Class B (Secretin family)

The class B secretin GPCR (SecR), a subfamily of GPCRs, has broad physiological effects, since their endogenous ligands play major roles in homeostatic control of bone and energy metabolism, cardiovascular, and immune responses. Therefore, secretin GPCR has the target potential for treatment of metabolic and cardiovascular disease. Class B GPCRs encompass targets for approved drugs that treat diabetes, obesity, osteoporosis, hypercalcemia, and Paget's disease, all of which are major global health burdens. The understanding of SecR binding and activation from a molecular perspective is of great significance for the development of drugs for the treatment of related diseases.

--Class C (Orphan GPCR)

At present, orphan GPCR is a class of GPCR receptors whose function and endogenous ligands are unknown. GPR158, a class C orphan GPCR, functions in cognition, stress-induced mood control, and synaptic development. GPR158 is unique as it lacks a Venus flytrapfold ligand-binding domain and localizes RGS7–Gβ5 and the Gαi/o protein activated by other GPCRs, and allosterically promotes GTPase activity of Gαi/o, which ultimately reduces the activity of adenylate cyclase and controls other signaling pathways including neuronal G protein signaling, etc. RGS7 plays a critical role in the nervous system where it regulates multiple neurotransmitter GPCRs that mediate vision, memory, and the action of addictive drugs, which provides a new idea for drug intervention of mental diseases.

G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are major targets for drug discovery, which provides a new research idea for drug intervention therapy of mental diseases, cancers, etc. In addition, harnessing the sensing capability of GPCRs could have profound implications for biotechnology, enabling specific detection of an immense diversity of ligands.