G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.

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 include the central ligand-binding pocket of GPCR. In contrast, the heterotrimeric G protein binding site is the third cytosolic loop.

Ligand binding induces the GPCRs to undergo a conformational change and bind 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, chemokine receptors, and beta-adrenergic receptors.
• Class B comprises hormone-binding receptors such as 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 detect hormones, growth factors, or endogenous ligands, while several others are involved in olfactory and gustatory responses. One commonly used class of drugs, beta-blockers, target beta-adrenergic receptors and treat conditions such as hypertension, cardiac arrhythmia, and anxiety. GPCRs provide an effective target to create an arsenal for various diseased conditions.