Large-conductance voltage- and Ca2+-activated potassium (BK) channels are critical modulators of cellular excitability throughout the cardiovascular and nervous systems. The first aim of this work focuses on a novel role for BK channels in regulating cardiac pacing. Recently, BK channels were implicated in heart rate regulation, but the underlying mechanism was unclear. We hypothesized that BK channels regulate heart rate by modulating the intrinsic excitability of sinoatrial node cells (SANCs), the predominant cardiac pacemaking cells. We found that BK channel protein was expressed in SANCs, and that elimination of BK currents via pharmacological inhibition and genetic ablation reduces SANC excitability. Additionally, we characterized the properties of BK currents from SANCs. Our results indicate that BK channels are novel regulators of SANC function, and suggest that BK channels can serve as a novel therapeutic target for treating heart rate disorders.

The second aim of this work focuses on the effect of single-nucleotide polymorphisms (SNPs) on BK current properties. There are approximately 100 known non-synonymous SNPs in human KCNMA1, the gene that encodes BK channels, but few have been characterized or linked with disease. We hypothesized that SNPs in KCNMA1 associated with disease, or located in domains of the BK channel gating ring that mediate Ca2+-dependent activation would alter BK current properties. We determined that the effects of SNPs on BK current properties were Ca2+ concentration-dependent. Also, we found that SNP-induced alterations in current kinetics influenced the amplitude of BK currents evoked by action potential waveforms. These results indicate that SNPs in KCNMA1 can modulate BK current properties and could contribute to the diversity of BK currents evoked by physiological stimuli.