TY - JOUR T1 - Constitutive activation of a single effector pathway: evidence for multiple activation states of a G protein-coupled receptor. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 112 LP - 122 VL - 49 IS - 1 AU - D M Perez AU - J Hwa AU - R Gaivin AU - M Mathur AU - F Brown AU - R M Graham Y1 - 1996/01/01 UR - http://molpharm.aspetjournals.org/content/49/1/112.abstract N2 - A cysteine-to-phenylalanine mutation in the third transmembrane domain of the alpha 1B-adrenergic receptor constitutively activates the receptor, resulting in G protein coupling in the absence of agonist and activation of only a single effector pathway (phospholipase C but not phospholipase A2). This mutant receptor displays a higher affinity for the catecholamines, norepinephrine, and epinephrine, as well as for other phenethylamines, but not for imidazolines, a class of structurally distinct alpha agonists. Dose-response studies demonstrate a higher potency and intrinsic activity of phenethylamines for polyphosphoinositide turnover but not for arachidonic acid release. Imidazolines have wild-type potencies and intrinsic activities for both pathways. These data indicate that a single receptor subtype forms multiple conformations (i.e., exhibits induced conformational pleiotropy) for G protein interactions (high affinity states) that are specific for a particular G protein/effector pathway and that multiple binding sites exist for agonists, which promote or induce these specific interactions. Pharmacological diversity may, thus, be achieved through a single receptor by the development of compounds that induce a single activated conformer. This has major ramifications for the eventual development of signaling-specific therapeutics. ER -