G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.

GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three cytosolic loops. Together with the extracellular loops, the transmembrane alpha-helices form the central ligand-binding pocket of GPCR. In contrast, the third cytosolic loop functions as the heterotrimeric G protein binding site.

Ligand binding activates the GPCRs as it undergoes a conformational change and also binds heterotrimeric G proteins with high affinity. An activated GPCR can bind and activate multiple G proteins to amplify the signal. G proteins, in turn, bind and activate downstream effectors and bring about a cellular response.

Although structurally, all mammalian GPCRs consist of seven transmembrane alpha-helical domains, they differ considerably in their sequence and functionality. GPCRs are broadly categorized into five classes, including Class A (rhodopsin-like), Class B (secretin receptor-like or B1), Class B2/ adhesion type, Class C (glutamate receptor-like), and Class F (frizzled-like).

• Class A forms the largest subfamily of GPCRs that includes rhodopsins and beta-adrenergic receptors.
• Class B comprises the hormone-binding receptors like glucagon, parathyroid hormone, and vasoactive intestinal peptide (VIP) receptors.
  • The adhesion or B2 receptor class includes the adhesion G protein-coupled receptors or ADGR groups of receptors such as ADGRL1 and ADGRG1 that are essential for cell adhesion and migration.
• Class C includes calcium-sensing receptors, gamma-aminobutyric acid (GABA) type B receptors, metabotropic glutamate receptors, and several taste receptors. Unlike the others, this group uses a characteristic venus fly trap module for ligand binding.
• Class F, also called frizzled-like, includes smoothened or Smo receptors and functions in embryonic development.

Overall, humans consist of more than 800 GPCRs. Many of these detect hormones, growth factors, or endogenous ligands, while several others are involved in olfactory and gustatory responses.

Thus, GPCRs regulate critical physiological pathways and are an excellent drug target for treating diseases like diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs. One commonly used class of drugs, beta-blockers, target beta-adrenergic receptors and treat conditions like hypertension, cardiac arrhythmia, and anxiety. GPCRs provide an effective target to create an arsenal for a varied range of diseased conditions.