Our laboratory is focused pacemaker ion channels. Pacemaker channels – also known as hyperpolarization-activated cyclic nucleotide-gated or HCN channels because they are activated by hyperpolarization of the membrane potential and are modulated by the direct binding of cyclic nucleotides – are important for regulating repetitive activity and conduction in the heart, but also contribute to cellular membrane potential in other types of tissue. Four genes code for the protein subunits that form HCN channels and four individual subunits subunits are required to make one channel. The importance of HCN channels in the heart beat is underscored by recent studies that have associated mutations in the channels with sinus dysfunction and arrhythmias. Furthermore, the inhibition of pacemaker channels by specific drugs is now used to treat angina and tachycardia e.g. ivabradine, a specific blocker of HCN channels,is now used clinically in France. Heart rate slowing is an important therapeutic approach to treat certain cardiac pathologies such as angina. Finally, modulation of HCN channels by the autonomic nervous system contributes to increases and decreases in heart rate.
Our interests in pacemaker channels cover three major areas. First, we are interested in the structure of the channels and how this structure influences channel responses to voltage and ion permeation through the channel pore. Second, we study factors that regulate cell surface number, localization, co-assembly and trafficking of the channels in cells, including sinoatrial myocytes and neurons. Third, we are interested in the evolution of HCN channels. This includes the functional analysis of channels from pre-vertebrate species and bioinformatics-based approaches to uncover novel channel sequences, analyze channel phylogeny and understand co-evolution of channels structure and function. Information from all of these projects is of clinical interest; we wish to understand how pacemaker channel dysfunction and dyslocalization are related to cardiovascular and central nervous system diseases such as sinus arrythmias and epilepsy, and to uncover ways in which pacemaker channels can be modulated to ameliorate these diseases. A variety of approaches have been developed in the lab to study pacemaker channels. These include protein biochemistry, confocal and wide-field imaging, site-directed mutagenesis/subcloning, patch clamp electrophysiology, and analyses of molecular evolution. We utilize heterologous cellular systems as well as isolated cells and tissues to carry out many of these studies.