Functional selectivity of dopamine receptor agonists.: II.: Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs
Functional selectivity of dopamine receptor agonists.: II.: Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs
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DOI：
10.1124/jpet.301.3.1179
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发表时间：
2002-06-01
影响因子：
3.5
通讯作者：
Mailman, RB
中科院分区：
文献类型：
--
作者：
Kilts, JD;Connery, HS;Mailman, RB
D-2样多巴胺受体通过激活抑制性G蛋白，包括那些影响腺苷环化酶活性的蛋白，以及钾和钙通道来介导功能变化。虽然假设药物与D-2样受体的单一亚型结合会导致受体介导的所有功能的类似变化，但在大脑中已证明多巴胺激动剂二氢呋喃(DHX)和N-正丙基-DHX是“功能选择性的”。目前的研究利用转基因的MN9D细胞和产生D-2的垂体前叶催乳素细胞来探索潜在的机制。多巴胺和DHX均以浓度依赖的方式抑制腺苷环化酶的活性，其作用可被D-2拮抗剂阻断，但不能被D-1拮抗剂阻断。在MN9D细胞中，奎比罗和R-(-)N-丙基去甲吗啡(NPA)也以浓度反应、拮抗剂可逆的方式抑制K+刺激的[H-3]多巴胺的释放。相反，DHX或其类似物都不能抑制K+刺激的[H-3]多巴胺的释放，尽管它们拮抗了奎比罗的作用。S-(+)-NPA实际上具有与DHX相反的功能选择性(即，它是D-2L受体上的完全激动剂，并能抑制多巴胺的释放，但在D-2L受体介导的腺苷环化酶抑制上，它是弱的部分激动剂)。在哺乳细胞中，DHX在与G蛋白偶联的内向整流钾通道偶联的D-2受体上几乎没有内源性活性，实际上拮抗了多巴胺在这些D-2受体上的作用。总之，这些发现为激动剂诱导D-2L受体的功能选择性提供了令人信服的证据。虽然潜在的分子机制是有争议的(例如，“构象诱导”和“药物活性状态选择”)，但这些数据与药物具有“内在疗效”的广泛观点是不一致的。
D-2-like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D-2-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-n-propyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D-2-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D-2, but not D-1, antagonists. In the MN9D cells, quinpirole and R-(-) N- propylnorapomorphine (NPA) also inhibited the K+ stimulated release of [H-3] dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K+-stimulated [H-3] dopamine release, although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D-2L receptors coupled to inhibition of dopamine release, but a weak partial agonist at D-2L receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D-2 receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D-2 receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D-2L receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".