Analysis of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function in adult heart using conditional transgenic mouse models

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The sinoatrial node (SAN) is the physiological pacemaker of the heart and is predominantly responsible for autonomous heart beat generation. Heart rate control is achieved through control of SAN pacemaking by the autonomic nervous system, and sinus node dysfunction is a major cause for pacemaker implantation in humans. A major depolarizing current in SAN cells, If, has been proposed to act as the primary pacemaker under physiological conditions, but direct evidence for such a function is still missing, since loss-of-function mouse mutants lacking If die during embryonic stages of development. If is mediated by cAMP-binding HCN channels. To overcome the limitation of embryonic lethality in HCN knockout animals, we will use conditional transgenic mouse lines with functionally (dominant negative mutations) and reversibly (Tet-Off system) inactivated HCN pacemaker channels. With these mouse lines we plan to study the physiological and pathophysiological roles of HCN channels in cardiac pacemaking, autonomic control, conduction, contractility, and adaptation to increased workload in the adult heart.