Grant: Operating Grant

This grant focuses on "pacemaker" channels, a special class of protein tubes found in large amounts on the surface of pacemaker cells of the sino-atrial (SA) node of the heart. The SA node is the primary pacemaker and sets the natural beating rate. When pacemaker channels open, they produce electrical activity that helps cells to contract and beat. Pacemaker channels also contribute to changes in heartbeat that occur in response to hormones such as adrenaline, which is released during the "fight or flight" response to a stressor. Adrenaline triggers the production of a small molecule, cyclic (c)AMP, inside the pacemaker cell which then attaches itself to the channel, allowing it to open more easily. Greater electrical activity and a faster beating rate result, permitting an adaptive, heightened physical reaction to the stressor. The way cAMP facilitates pacemaker channel opening has been actively studied, but findings are mainly inferred from the impact of this molecule on channel function. Specific determinants for binding of cAMP to the pacemaker channel, the strength and nature of this interaction, and the process by which function is altered remain unknown. In this application, direct binding approaches are implemented to understand the process by which cAMP facilitates channel opening. Importantly, we will measure the strength with which cAMP attaches itself to the channel using an approach called calorimetry in which the very small amounts of heat that are released when the two molecules interact are directly measured. This is the first time calorimetry has been utilized successfully with pacemaker channels; together with concurrent analyses of channel function, direct assessments of binding by calorimetry will greatly aid in the design of new drugs and therapeutic strategies to control heart rate, disorders of which include abnormally slowed or increased heart rate, pauses, and arrest with the associated risk for compromised quality of life and even death.