An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel
An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel
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DOI：
10.1073/pnas.1317363111
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发表时间：
2014-06-24
影响因子：
11.1
通讯作者：
Dopico, Alex M.
中科院分区：
文献类型：
--
作者：
Bukiya, Anna N.;Kuntamallappanavar, Guruprasad;Dopico, Alex M.
乙醇改变BK（slo 1）通道功能，导致生理和行为的扰动。乙醇-BK通道相互作用的位点和机制未知。我们证明，乙醇停靠在一个水可访问的网站，战略定位之间的SLO 1钙传感器和门。乙醇只有在钙离子存在的情况下才能到达这个部位，钙离子是BK通道的生理激动剂。在该位点内，乙醇与K361形成氢键。此外，阻碍氢键形成或阻止乙醇进入K361的取代在不改变基础通道功能的情况下消除了醇的作用。醇相互作用位点尺寸约为10.7 × 8.6 × 7.1埃，可容纳有效（乙醇-庚醇）但非无效（辛醇、壬醇）通道激活剂。这项研究提出：（i）据我们所知，第一次鉴定和表征了电压门控TM 6通道超家族成员中的正烷醇识别位点;（ii）对乙醇与配体门控离子通道的变构相互作用的结构见解;和（iii）设计拮抗BK通道介导的醇作用而不干扰基础通道功能的试剂的第一步。
Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 x 8.6 x 7.1 angstrom, accommodating effective (ethanol- heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.