Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior.
Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior.
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DOI：
10.3389/fphys.2014.00466
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发表时间：
2014
影响因子：
4
通讯作者：
Martin GE
中科院分区：
文献类型：
--
作者：
Dopico AM;Bukiya AN;Martin GE
在大多数组织中，Ca2+- 和电压门控 K+ (BK) 通道的功能会根据酒精中毒期间人体血液中达到的乙醇浓度而发生改变。一般来说，响应于短暂的乙醇暴露，未接触乙醇的制剂中的 BK 电流的改变是由于通道开放概率的变化而导致的，而没有改变单一电导或膜中 BK 蛋白水平的变化。然而，长期和/或反复接触乙醇可能会引起 BK 表达的变化。乙醇对 BK 打开概率的最终影响导致 BK 电流增强或 BK 电流减少，这是由分子因素的协调决定的，包括激活配体 (Ca2+i) 的水平、BK 亚基组成和翻译后修饰以及通道的脂质微环境。这些因素似乎以变构方式调节乙醇和最近映射到通道形成（slo1）亚基的离散尺寸识别袋之间的直接相互作用。乙醇暴露的类型也在 BK 对药物的最终反应中发挥作用：在几个中枢神经系统区域（例如纹状体、初级感觉神经元和视上核），急性暴露于乙醇会通过增强 BK 活性来降低神经元兴奋性。相反，长期或重复的乙醇施用可能会改变 BK 亚基组成和膜表达，使 BK 复合物对进一步的乙醇暴露不敏感。在神经垂体轴突末端，乙醇增强 BK 通道活性导致神经肽释放减少。然而，在血管平滑肌中，乙醇抑制 BK 电流会导致细胞收缩和血管收缩。
In most tissues, the function of Ca2+- and voltage-gated K+ (BK) channels is modified in response to ethanol concentrations reached in human blood during alcohol intoxication. In general, modification of BK current from ethanol-naïve preparations in response to brief ethanol exposure results from changes in channel open probability without modification of unitary conductance or change in BK protein levels in the membrane. Protracted and/or repeated ethanol exposure, however, may evoke changes in BK expression. The final ethanol effect on BK open probability leading to either BK current potentiation or BK current reduction is determined by an orchestration of molecular factors, including levels of activating ligand (Ca2+i), BK subunit composition and post-translational modifications, and the channel's lipid microenvironment. These factors seem to allosterically regulate a direct interaction between ethanol and a recognition pocket of discrete dimensions recently mapped to the channel-forming (slo1) subunit. Type of ethanol exposure also plays a role in the final BK response to the drug: in several central nervous system regions (e.g., striatum, primary sensory neurons, and supraoptic nucleus), acute exposure to ethanol reduces neuronal excitability by enhancing BK activity. In contrast, protracted or repetitive ethanol administration may alter BK subunit composition and membrane expression, rendering the BK complex insensitive to further ethanol exposure. In neurohypophyseal axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release. In vascular smooth muscle, however, ethanol inhibition of BK current leads to cell contraction and vascular constriction.
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DOI：
10.1073/pnas.1317363111
发表时间：
2014-06-24
影响因子：
11.1
作者：
Bukiya, Anna N.;Kuntamallappanavar, Guruprasad;Dopico, Alex M.
通讯作者：
Dopico, Alex M.
影响因子：
3.5
作者：
Bukiya, Anna N.;Liu, Jianxi;Dopico, Alejandro M.
通讯作者：
Dopico, Alejandro M.
影响因子：
56.9
作者：
CARLEN, PL;GUREVICH, N;DURAND, D
通讯作者：
DURAND, D
影响因子：
4.8
作者：
Brenner, R;Jegla, TJ;Aldrich, RW
通讯作者：
Aldrich, RW
影响因子：
21.1
作者：
Dopico AM;Lovinger DM
通讯作者：
Lovinger DM