The rs13376333 risk allele mimics the effect of atrial fibrillation on SK-current density and afterdepolarizations in human atrial myocytes

Abstract Background Various genome wide association studies have associated the single nucleotide polymorphism (SNP) rs13376333 with increased risk of atrial fibrillation. This SNP is intronic to KCNN3 gene that codes for small conductance calcium-activated potassium channel type 3 (SK3), but functional electrophysiological effects variant are not known. Purpose study aimed fibrillation and on apamine sensitive SK-current afterdepolarizations in human myocytes. Methods Myocytes were isolated from right samples, subjected perforated patch-clamp technique measure (100 nM) elicited by a voltage-ramp protocol, spontaneous transient inward Na-Ca exchange currents (ITI) or at rest. To assess impact variant, patients without genotyped divided into control groups according genotype rs13376333. Results At membrane potentials above −40 mV, density increasing potentials. +20mV was significantly smaller (0.18±0.04 pA/pF) 5 than 24 this arrhythmia (0.65±0.12 pA/pF, p<0.01). On other hand, ITI larger 10 23 (0.71±0.16 vs. 0.30±0.03 p<0.01), supporting notion myocytes cannot counter-balance calcium-release induced ITI, resulting net higher incidence detectable these patients. In line notion, inhibition 100 nM frequency afterdepolarization between −85 −75 mV 1.2±0.3 2.5±0.5 events/min (p=0.03) Analysis current-voltage relationship showed presented apamine-sensitive SK current (p<0.001, n=15). +20 SK-density 60% carrying allele (0.43±0.18 1.08±0.27 mimicking depression observed Conclusion Both reduced myocytes, which may contribute conditions. Thus, restoration SK-channel function rs1337633 help reduce Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Spanish Ministry Science Innovation