Bett Glenna C L, Rasmusson Randall L
Center for Cellular and Systems Electrophysiology, Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, 124 Sherman Hall, State University of New York at Buffalo, Buffalo, NY 14214-3005, USA.
J Physiol. 2008 Feb 15;586(4):929-50. doi: 10.1113/jphysiol.2007.139279. Epub 2007 Dec 20.
Reconciling ion channel alpha-subunit expression with native ionic currents and their pharmacological sensitivity in target organs has proved difficult. In native tissue, many K(+) channel alpha-subunits co-assemble with ancillary subunits, which can profoundly affect physiological parameters including gating kinetics and pharmacological interactions. In this review, we examine the link between voltage-gated potassium ion channel pharmacology and the biophysics of ancillary subunits. We propose that ancillary subunits can modify the interaction between pore blockers and ion channels by three distinct mechanisms: changes in (1) binding site accessibility; (2) orientation of pore-lining residues; (3) the ability of the channel to undergo post-binding conformational changes. Each of these subunit-induced changes has implications for gating, drug affinity and use dependence of their respective channel complexes. A single subunit may modulate its associated alpha-subunit by more than one of these mechanisms. Voltage-gated potassium channels are the site of action of many therapeutic drugs. In addition, potassium channels interact with drugs whose primary target is another channel, e.g. the calcium channel blocker nifedipine, the sodium channel blocker quinidine, etc. Even when K(+) channel block is the intended mode of action, block of related channels in non-target organs, e.g. the heart, can result in major and potentially lethal side-effects. Understanding factors that determine specificity, use dependence and other properties of K(+) channel drug binding are therefore of vital clinical importance. Ancillary subunits play a key role in determining these properties in native tissue, and so understanding channel-subunit interactions is vital to understanding clinical pharmacology.
事实证明，要使离子通道α亚基的表达与靶器官中的天然离子电流及其药理学敏感性相匹配并非易事。在天然组织中，许多钾离子通道α亚基与辅助亚基共同组装，这会深刻影响包括门控动力学和药理学相互作用在内的生理参数。在这篇综述中，我们研究了电压门控钾离子通道药理学与辅助亚基生物物理学之间的联系。我们提出，辅助亚基可通过三种不同机制改变孔道阻滞剂与离子通道之间的相互作用：（1）结合位点可及性的变化；（2）孔道内衬残基的取向；（3）通道进行结合后构象变化的能力。这些由亚基引起的每种变化都对各自通道复合物的门控、药物亲和力和使用依赖性具有影响。单个亚基可能通过不止一种这些机制来调节其相关的α亚基。电压门控钾通道是许多治疗药物的作用位点。此外，钾通道还与主要靶点为其他通道的药物相互作用，例如钙通道阻滞剂硝苯地平、钠通道阻滞剂奎尼丁等。即使钾离子通道阻滞是预期的作用方式，非靶器官（如心脏）中相关通道的阻滞也可能导致严重且潜在致命的副作用。因此，了解决定钾离子通道药物结合特异性、使用依赖性和其他特性的因素具有至关重要的临床意义。辅助亚基在决定天然组织中的这些特性方面起着关键作用，所以了解通道 - 亚基相互作用对于理解临床药理学至关重要。
