Perez D M, Hwa J, Gaivin R, Mathur M, Brown F, Graham R M
Department of Molecular Cardiology, Cleveland Clinic Research Institute, Ohio 44195, USA.
Mol Pharmacol. 1996 Jan;49(1):112-22.
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.
α1B - 肾上腺素能受体第三个跨膜结构域中的半胱氨酸到苯丙氨酸突变可组成性激活该受体，导致在无激动剂的情况下发生G蛋白偶联，且仅激活单一效应器途径（磷脂酶C而非磷脂酶A2）。这种突变受体对儿茶酚胺、去甲肾上腺素和肾上腺素以及其他苯乙胺显示出更高的亲和力，但对咪唑啉（一类结构不同的α激动剂）则不然。剂量反应研究表明，苯乙胺对多磷酸肌醇周转具有更高的效力和内在活性，但对花生四烯酸释放则不然。咪唑啉对这两种途径具有野生型效力和内在活性。这些数据表明，单一受体亚型形成了多种构象（即表现出诱导的构象多效性）用于与特定G蛋白/效应器途径特异性相关的G蛋白相互作用（高亲和力状态），并且激动剂存在多个结合位点，这些位点促进或诱导这些特异性相互作用。因此，通过开发诱导单一活化构象的化合物，单一受体可能实现药理学多样性。这对信号特异性治疗药物的最终开发具有重大影响。
