β2 and β4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones
β2 and β4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones
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DOI：
10.1152/jn.01352.2005
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发表时间：
2006-05-01
影响因子：
2.5
通讯作者：
McCobb, DP
中科院分区：
文献类型：
--
作者：
King, JT;Lovell, PV;McCobb, DP
用于快速类固醇神经调节的膜相关受体仍然难以捉摸。据报道，如果与 β1 亚基相关，雌二醇可促进由 Slo 编码的电压和 Ca2+ 依赖性 BK 钾通道的激活。我们在此表明：1）β 家族的多个成员赋予 BK 通道上对多种类固醇的敏感性，2）β 亚基在类固醇之间进行区分，3）不同的 β 对特定类固醇有不同的相对偏好。在 HEK 293 细胞中表达的具有仅由 Slo-alpha 组成的通道的内向外斑块显示出没有类固醇敏感性。表达αβ4的细胞表现出皮质酮（CORT；一种糖皮质激素）的强效、快速、可逆和剂量依赖性增强作用，而其他性别和应激类固醇的增强作用程度较小。相比之下，脱氢表雄酮（DHEA；一种神秘的、与压力相关的肾上腺雄激素）对 αβ2 通道的增强作用更强，而 CORT、雌二醇、睾酮和 DHEA-S 的增强程度较小。胆固醇对任何测试的 BK 通道组合物没有影响。由 α 加 β 2 或 β 4 亚基组成的通道的电导-电压图因类固醇而向负方向移动，表明负电压下有更大的激活。因此，我们的结果表明，体内发生的 Slo-β 亚基共表达模式的多样性在另一个尚未完全理解的维度上扩展了 Slo 通道门控的全部功能，使得 BK 门控对多种类固醇激素的动态波动做出响应。
Membrane-associated receptors for rapid, steroidal neuromodulation remain elusive. Estradiol has been reported to facilitate activation of voltage- and Ca2+-dependent BK potassium channels encoded by Slo, if associated with beta 1 subunits. We show here that 1) multiple members of the beta family confer sensitivity to multiple steroids on BK channels, 2) that beta subunits differentiate between steroids, and 3) that different beta s have distinct relative preferences for particular steroids. Expressed in HEK 293 cells, inside-out patches with channels composed of Slo-alpha alone showed no steroid sensitivity. Cells expressing alpha beta 4 exhibited potent, rapid, reversible, and dose-dependent potentiation by corticosterone (CORT; a glucocorticoid), and were potentiated to a lesser degree by other sex and stress steroids. In contrast, alpha beta 2 channels were potentiated more strongly by dehydroepiandrosterone (DHEA; an enigmatic, stress-related adrenal androgen), and to a lesser extent by CORT, estradiol, testosterone, and DHEA-S. Cholesterol had no effect on any BK channel compositions tested. Conductance-voltage plots of channels composed of alpha plus beta 2 or beta 4 subunits were shifted in the negative direction by steroids, indicating greater activation at negative voltages. Thus our results argue that the variety of Slo-beta subunit coexpression patterns occurring in vivo expands the repertoire of Slo channel gating in yet another dimension not fully appreciated, rendering BK gating responsive to dynamic fluctuations in a multiple of steroid hormones.