Abstract 17405: Small K+ Channel Activity Modulates Sinoatrial Node Pacemaker Rate and Explains the Abnormal Bursts of Sinoatrial Node Pacing in Atrial-Specific Na+/Ca2+ Exchange Knockout Mice
Rationale: Ca2+-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.
Objective: To prove SK expression in murine SAN, and to investigate their ability to translate diastolic Ca2+ variation into membrane voltage changes during normal and pro-arrhythmic SAN automaticity.
Methods and results: Immunostaining, 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 Ca2+ changes, we compared their activity in control mice and in a mouse model of SAN cell diastolic Ca2+ overload, resulting from atrial-specific ablation of the Na+/Ca2+ 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 Ca2+ 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 Ca2+ buffering in this model, consistent with an effect of elevated Ca2+ on beating pattern. Big K+ channel (BK) inhibition with paxilline had no effect on NCX KO SAN rate.
Conclusions: SK channels modulate APD and SAN pacemaker rate, and can modulate baseline rhythmic activity. Their Ca2+-dependent activation quickly translates Ca2+ 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 Ca2+ 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 Ca2+.
Author Disclosures: A.G. Torrente: None. R. Zhang: None. H. Wang: None. A. Zaini: None. B.Y. Kim: None. K.D. Philipson: None. J.I. Goldhaber: None.
- © 2016 by American Heart Association, Inc.