Abstract
Small-conductance Ca2+-activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca2+ microdomains necessary for SK channel activation. SK currents coupled with Ca2+ influx via L-type Ca2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca2+ store, suggesting that LTCCs provide the immediate Ca2+ microdomain for the activation of SK channels in cardiomyocytes. Super-resolution imaging of SK2, Cav1.2 Ca2+ channel, and ryanodine receptor 2 (RyR2) was performed to quantify the nearest neighbor distances (NND) and localized the three molecules within hundreds of nanometers. The distribution of NND between SK2 and RyR2 as well as SK2 and Cav1.2 was bimodal, suggesting a spatial relationship between the channels. The activation mechanism revealed by our study paved the way for the understanding of the roles of SK channels on the feedback mechanism to regulate the activities of LTCCs and RyR2 to influence local and global Ca2+ signaling.
Highlights
Small-conductance Ca2+-activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis
Apamin-sensitive SK currents were previously identified in mouse and human hearts to play critical roles in atrial repolarization[3]
SK channels contribute to cardiac repolarization, participate in electrical remodeling in heart failure and atrial fibrillation, and may serve as potential therapeutic targets against cardiac arrhythmias[4,5,6,7]
Summary
Small-conductance Ca2+-activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. Main ion channels and transporters of Ca2+ into and out of the cells and intracellular Ca2+ stores include Ca2+ channels, Na+/Ca2+ exchanger, ryanodine receptor 2 (RyR2), and sarcoplasmic reticulum (SR) Ca2+-ATPase The function of these molecules are orchestrated by a network of subcellular signaling molecules including calmodulin (CaM), Ca2+/CaM-dependent protein kinase II (CaMKII), phospholamban (PLB), cAMP, and protein kinase A (PKA). Our previous studies revealed that cardiac SK2 channels coupled with L-type Ca2+ channels (LTCCs) through a physical bridge, α-actinin[2], suggesting that LTCCs may functionally regulate SK2 channels by providing local Ca2+ domain to activate the SK channels[13]. Another study reported that inhibition or knockdown of RyR2 or depletion of SR Ca2+ store significantly reduced SK currents in mouse atrial myocytes[15] Both studies support the importance of RyR2 in the activation of cardiac SK channels
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