Structure of α6β3δ GABAA receptors and their lack of ethanol sensitivity
Structure of α6β3δ GABAA receptors and their lack of ethanol sensitivity
复制标题
DOI：
10.1111/j.1471-4159.2009.06387.x
复制
发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Sigel, Erwin
中科院分区：
文献类型：
--
作者：
Baur, Roland;Kaur, Kuldeep H.;Sigel, Erwin
含有 GABA(A) 受体的 Delta (δ) 亚基在突触外表达并介导强直抑制。在小脑颗粒细胞中，它们通常与 α(6) 亚基一起形成受体。我们有兴趣确定这些受体的结构。我们通过亚基串联预定义了 24 个不同的 GABA(A) 受体五聚体的亚基排列。这些受体（由 α(6)、β(3) 和 δ 亚基组成）在非洲爪蟾卵母细胞中表达，并分析了它们的电生理特性。在存在和不存在 3α,21-二羟基-5α-孕-20-酮和 4,5,6,7-四氢异恶唑并[5,4-c]-吡啶-3-醇的情况下测定响应 GABA 引起的电流。 α(6)-β(3)-α(6)/δ 受体对单独的 GABA 表现出显着的反应。三种受体：β(3)-α(6)-δ/α(6)-β(3)、α(6)-β(3)-α(6)/β(3)-δ和β(3)-δ-β(3)/α(6)-β(3)仅在神经类固醇3α、21-二羟基-5α-孕-20-一与GABA联合存在时才被发现。所有四种受体均被 4,5,6,7-四氢异恶唑并[5,4-c]-pyridin-3-ol 激活。没有一个功能受体受到生理浓度（高达 30 mM）的乙醇的调节。 GABA 浓度响应曲线表明 delta 亚基有助于激动剂位点的形成。我们从所研究的受体中得出结论，δ亚基可以在由α(6)、β(3)和δ亚基组成的受体五聚体中占据多个位置。
Delta (delta) subunit containing GABA(A) receptors are expressed extra-synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with alpha(6) subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABA(A) receptor pentamers by subunit concatenation. These receptors (composed of alpha(6), beta(3) and delta subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one and to 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. alpha(6)-beta(3)-alpha(6)/delta receptors showed a substantial response to GABA alone. Three receptors, beta(3)-alpha(6)-delta/alpha(6)-beta(3), alpha(6)-beta(3)-alpha(6)/beta(3)-delta and beta(3)-delta-beta(3)/alpha(6)-beta(3), were only uncovered in the combined presence of the neurosteroid 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one with GABA. All four receptors were activated by 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the delta subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the delta subunit can assume multiple positions in a receptor pentamer composed of alpha(6), beta(3) and delta subunits.