Résumé
RationaleCa-sensitive small K (SK) channels have been implicated in abnormal atrial repolarization, automaticity and conduction in the heart. Despite their potential role in sinoatrial node (SAN) dysfunction, their presence and contribution to SAN pacemaker activity are unknown.ObjectiveTo prove SK expression in murine SAN, and to investigate their ability to translate diastolic Ca variation into membrane voltage changes during normal and pro-arrhythmic SAN automaticity.Methods and resultsImmunostaining, quantitative-PCR and patch clamp recordings demonstrated functional presence of all SK isoforms (SK1, SK2 and SK3) in the SAN. Since SK channels are exquisitely sensitive to Ca changes, we compared their activity in control mice and in a mouse model of SAN cell diastolic Ca overload, resulting from atrial-specific ablation of the Na/Ca exchanger (NCX KO). Wildtype (WT) littermates were used as control (equal ratio M/F). In WT SAN cells, induced and spontaneous action potentials (APs), were prolonged by the SK specific inhibitor Apamin (10 nM). NCX KO SAN cells showed stronger baseline SK current at depolarized potentials, consistent with the shorter AP duration (APD) compared to WT. As in WT, Apamin increased APD in KO. High speed 2D confocal Ca imaging revealed slowing of SAN rate in WT tissue treated with Apamin (10 nM), and regularization of the previously published abnormal burst pacing pattern characterizing NCX KO. The regularization of the beating pattern in KO is similar to the effects of Ca buffering in this model, consistent with an effect of elevated Ca on beating pattern. Big K channel (BK) inhibition with paxilline had no effect on NCX KO SAN rate.ConclusionsSK channels modulate APD and SAN pacemaker rate, and can modulate baseline rhythmic activity. Their Ca-dependent activation quickly translates Ca transients into additional repolarizing current necessary to complete the AP and induce the following spontaneous diastolic depolarization. SK channel inhibition effectively reduces the burst pacing induced by elevated diastolic Ca in the NCX KO SAN. These results suggest that SK channels may be an effective target for treating SAN dysfunction, which is often associated with elevated Ca.