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G protein-coupled receptors (GPCRs) are integral membrane proteins containing an extracellular amino terminus, seven transmembrane α-helical domains, and an intracellular carboxy terminus. GPCRs recognize a wide variety of signals ranging from photons to ions, proteins, neurotransmitters, and hormones. The human genome encodes nearly 800 GPCRs, representing over 3% of human genes. The GPCR superfamily comprises at least five structurally distinct subfamilies: Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin receptor families. About 90% of all GPCRs belong to the rhodopsin family. [1] Impaired ligand concentration, GPCR protein expression, or mutation and signaling are implicated in many pathophysiological conditions, including central nervous system (CNS) disorders, cardiovascular and metabolic diseases, respiratory malfunctions, gastrointestinal disorders, immune diseases, cancer, musculoskeletal pathologies, and eye diseases. Targeting of GPCRs is hence widely utilized for therapeutic intervention; GPCRs correspond to 30% of all identified drug targets and remain major targets for new drug development.[2][3] Signal transduction through G proteins is the most prominent feature of GPCRs, initiated by a ligand-GPCR interaction at the cell surface level.

More than 30 human diseases and syndromes are potentially associated with the loss or gain of GPCRs caused by mutations. Mutational activation of GPCR (ie, constitutively activating mutations), such as mutations in an α1B-adrenergic receptor, specifically enhances receptor/G protein coupling in the absence of agonist ligands which could lead to cellular transformation and cancer. Certain inherited diseases, such as autosomal dominant non-autoimmune hyperthyroidism, are caused by activating mutations in the TSH receptor gene. Similarly, a gain of function mutation in the LHR gene is known to cause a gonadotropin-releasing hormone (GnRH)-independent precocious puberty in boys, also called familial male-limited precocious puberty (FMPP) or testotoxicosis. Jansen's metaphyseal chondrodysplasia is a rare autosomal dominant form of short-limb dwarfism caused by activating mutations in the PTH/PTHrP receptor.[15] Loss of function of GPCRs due to amino acid substitutions, truncations by nonsense or frameshift mutations, insertions, deletions, and rearrangements are also associated with many human diseases. For example, mutation of vasopressin V2 receptor (antidiuretic hormone receptor, AVPR2) and aquaporin 2 (AQP2) genes are linked to nephrogenic diabetes insipidus syndrome. Mutations in the Inactivating mutations in the rhodopsin (RHO) gene are the most common cause of retinitis pigmentosa (RP), which causes retinal dystrophy with early onset of night blindness and subsequent loss of the visual field.[16]