Amino acid domains involved in constitutive activation of G-protein-coupled receptors - Review

Guanine nucleotide-binding protein-coupled receptors may attain an active c onformation in the absence of agonist by spontaneous isomerization and thus yield constitutive, agonist-independent, activity. This has mainly been de monstrated for isolated membranes and recombinant wild-type receptors, and mutant receptors. They generally show remarkable increases in the sensitivi ty of a biological response. The location of activating mutations both with in a single receptor and across receptors is widespread, with changes repor ted in the seven-transmembrane domains, the second and third intracellular loop. For most of these receptors, examples of ligands defined as inverse a gonists have been documented. Regulation of these receptors by inverse agon ists opposite to that observed by agonists, and the therapeutic potential o f inverse agonists is underlined.