Division of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA.
J Neurochem. 2012 May;121(3):349-61. doi: 10.1111/j.1471-4159.2012.07685.x. Epub 2012 Mar 14.
The nicotinic acetylcholine receptor (nAChR) β3 subunit is thought to serve an accessory role in nAChR subtypes expressed in dopaminergic regions implicated in drug dependence and reward. When β3 subunits are expressed in excess, they have a dominant-negative effect on function of selected nAChR subtypes. In this study, we show, in Xenopus oocytes expressing α2, α3 or α4 plus either β2 or β4 subunits, that in the presumed presence of similar amounts of each nAChR subunit, co-expression with wild-type β3 subunits generally (except for α3*-nAChR) lowers amplitudes of agonist-evoked, inward peak currents by 20-50% without having dramatic effects (≤ 2-fold) on agonist potencies. By contrast, co-expression with mutant β3(V9'S) subunits generally (except for α4β2*-nAChR) increases agonist potencies, consistent with an expected gain-of-function effect. This most dramatically demonstrates formation of complexes containing three kinds of subunit. Moreover, for oocytes expressing nAChR containing any α subunit plus β4 and β3(V9'S) subunits, there is spontaneous channel opening sensitive to blockade by the open channel blocker, atropine. Collectively, the results indicate that β3 subunits integrate into all of the studied receptor assemblies and suggest that natural co-expression with β3 subunits can influence levels of expression and agonist sensitivities of several nAChR subtypes.
烟碱型乙酰胆碱受体 (nAChR) β3 亚基被认为在参与药物依赖和奖赏的多巴胺能区域表达的 nAChR 亚型中起辅助作用。当β3 亚基表达过剩时，它们对选定的 nAChR 亚型的功能具有显性负效应。在这项研究中，我们在表达 α2、α3 或 α4 以及 β2 或 β4 亚基的非洲爪蟾卵母细胞中表明，在假定存在每种 nAChR 亚基的相似量的情况下，与野生型β3 亚基共同表达通常（除了 α3*-nAChR 之外）会降低激动剂引发的内向峰值电流的幅度 20-50%，而对激动剂效力没有显著影响（≤2 倍）。相比之下，与突变体β3(V9'S)亚基共同表达通常（除了 α4β2*-nAChR 之外）会增加激动剂效力，与预期的功能获得效应一致。这最能证明包含三种亚基的复合物的形成。此外，对于表达含有任何α亚基加β4 和β3(V9'S)亚基的 nAChR 的卵母细胞，存在对开放通道阻滞剂阿托品敏感的自发通道开放。总的来说，这些结果表明β3 亚基整合到所有研究的受体组装体中，并表明与β3 亚基的天然共表达可以影响几种 nAChR 亚型的表达水平和激动剂敏感性。
