The Pharmacology of Two-Pore Domain Potassium Channels.
The Pharmacology of Two-Pore Domain Potassium Channels.
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DOI：
10.1007/164_2021_462
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发表时间：
2021-04
影响因子：
--
通讯作者：
Jordie M Kamuene;Yu Xu;L. Plant
中科院分区：
文献类型：
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作者：
Jordie M Kamuene;Yu Xu;L. Plant
双孔结构域钾通道由每个含有两个孔环部分的亚基形成。无论通道是在酵母还是在人类中枢神经系统中表达，两个亚基聚集在一起形成单个钾选择性孔。TOK1是1995年从酵母中克隆的第一个双结构域通道，此后不久，在人类基因组中鉴定出15个不同的K2P亚基。基于序列以及生理学或药理学相似性，将人K2P通道分为六个K2P亚家族。功能性K2P通道通过背景（或“泄漏”）K+电流，其在广泛的组织中形成细胞的膜电位和兴奋性。在这些年来，因为他们第一次被描述，经典的功能测定，后来再加上国家的最先进的结构和计算研究揭示了K2P通道门控的机制基础，响应特定的物理化学或药理学刺激。K2P通道在越来越多的疾病的病理生理学中发挥着关键作用，这一点越来越受到重视，这使得K2P通道成为药物发现的靶点。在这里，我们总结了最近的进展，解开K2P通道的结构，功能和药理学。
Two-pore domain potassium channels are formed by subunits that each contain two pore-loops moieties. Whether the channels are expressed in yeast or the human central nervous system, two subunits come together to form a single potassium selective pore. TOK1, the first two-domain channel was cloned fromSaccharomyces cerevisiaein 1995 and soon thereafter, 15 distinct K2Psubunits were identified in the human genome. The human K2Pchannels are stratified into six K2Psubfamilies based on sequence as well as physiological or pharmacological similarities. Functional K2Pchannels pass background (or “leak”) K+currents that shape the membrane potential and excitability of cells in a broad range of tissues. In the years since they were first described, classical functional assays, latterly coupled with state-of-the-art structural and computational studies have revealed the mechanistic basis of K2Pchannel gating in response to specific physicochemical or pharmacological stimuli. The growing appreciation that K2Pchannels can play a pivotal role in the pathophysiology of a growing spectrum of diseases makes a compelling case for K2Pchannels as targets for drug discovery. Here, we summarize recent advances in unraveling the structure, function, and pharmacology of the K2P channels.