Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

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.