Comparative studies on HCN channels

我的NSERC研究计划的长期目标是了解超极化激活的环核苷酸门控HCN通道在进化过程中的结构，功能和生理学。HCN通道亚基是超极化激活电流Ih的基础，Ih也被称为有趣电流（If）或起搏电流，因为其独特的生物物理性质及其对哺乳动物心脏自行跳动的能力的贡献。HCN通道是电压门控钾通道家族的成员，但它们通过膜电位的超极化缓慢激活，并允许大量的钠和钾流过孔。环AMP结合到C-末端的细胞内结构域促进不同程度的开放，这取决于HCN同种型。在接下来的五年里，我的研究重点是环核苷酸对HCN通道功能的调节。虽然cAMP被认为是促进HCN开放的主要环核苷酸，但现在有一些证据表明cGMP在某些条件下也可能很重要。此外，其他环核苷酸，如cIMP和cUMP，可能是体内HCN通道的调节剂。环核苷酸促进开放的分子机制以及促进程度在异构体和不同环核苷酸之间变化的原因仍不清楚。此外，如何在分子水平上确定环核苷酸的效力和选择性尚不清楚。本文提出的研究旨在确定环核苷酸结合如何促进开放，如何在分子水平上实现环核苷酸的效力和选择性，以及这些特征在进化过程中HCN变体之间的差异。

The long-term goal of my NSERC Research Program is to understand the structure, function and physiology of the hyperpolarization-activated cyclic nucleotide-gated HCN channel over evolutionary time. HCN channel subunits underlie the hyperpolarization-activated current Ih, also called the funny current (If) or the pacemaker current because of its unique biophysical properties and its contribution to the ability of the mammalian heart to beat on its own, respectively. HCN channels are members of the voltage-gated potassium channel family but they are slowly activated by hyperpolarization of the membrane potential and allow a significant amount of sodium, as well as potassium, to flow through the pore. Cyclic AMP binding to an intracellular domain in the C-terminus facilitates opening to variable degrees depending on the HCN isoform. My research over the next five years is focused on cyclic nucleotide modulation of HCN channel function. Although cAMP is thought to be the primary cyclic nucleotide that facilitates HCN opening, there is now some evidence that cGMP may also be important under some conditions. Furthermore, other cyclic nucleotides, such as cIMP and cUMP, may be modulators of HCN channels in vivo. The molecular mechanisms by which cyclic nucleotides facilitate opening and why the degree of facilitation varies among isoforms and different cyclic nucleotides remain unclear. Furthermore, how potency and selectivity of cyclic nucleotides is determined at the molecular level is not known. The research proposed here aims to determine how cyclic nucleotide binding facilitates opening, how potency and selectivity for cyclic nucleotides is achieved at the molecular level and how these features differ among HCN variants over the course of evolution.