부산대학교 도서관

Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current ([I.sub.f]) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify [I.sub.f] during the cardiac cycle in mouse SAMs. We found that [I.sub.f] is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2 to 5% of its maximal conductance, [I.sub.f] carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that [beta]-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by [I.sub.f], consistent with a contribution of [I.sub.f] to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of [I.sub.f]. Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of [I.sub.f] during the sinoatrial AP. These results establish a new conceptual framework for the role of [I.sub.f] in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions. cardiac pacemaking | HCN channel | funny current | AP clamp | sinoatrial node