Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites

Abstract

Objective: Atrial fibrillation is often initiated by bursts of ectopic activity arising in the pulmonary veins. We have previously shown that a 3-h intermittent burst pacing protocol (BPP), mimicking ectopic pulmonary vein foci, shortens action potential duration (APD) locally at the pulmonary vein-atrial interface (PV) while having no effect elsewhere in rabbit atrium. This shortening is Ca 2+ dependent and is prevented by apamin, which blocks small conductance Ca 2+ -activated K + channels (SK Ca ). The present study investigates the ionic and molecular mechanisms whereby two apamin-sensitive SK Ca channels, SK2 and SK3, might contribute to the regional APD changes. Methods: Microelectrode and patch clamp techniques were used to record APDs and apamin-sensitive currents in isolated rabbit left atria and cells dispersed from PV and Bachmann's bundle (BB) regions. SK2 and SK3 mRNA and protein levels were quantified, and immunofluorescence was used to observe channel protein distribution. Results: There was a direct relationship between APD shortening and apamin-sensitive current in burst-paced but not sham-paced PV. Moreover, apamin-sensitive current density increased in PV but not BB after BPP. SK2 mRNA, protein, and current were increased in PV after BPP, while SK2 immunostaining shifted from a perinuclear pattern in sham atria to predominance at sites near or at the PV membrane. Conclusions: BPP-induced acceleration of repolarization in PV results from SK2 channel trafficking to the membrane, leading to increased apamin-sensitive outward current. This is the first indication of involvement of Ca 2+ -activated K + currents in atrial remodeling and provides a possible basis for evolution of an arrhythmogenic substrate.

Significant Association of rs13376333 in KCNN3 on Chromosome 1q21 With Atrial Fibrillation in a Taiwanese Population

“…24 Later, 1 study implied a link between SK channels and AF pathogenesis by providing evidence that increased SK2 channel cell-membrane trafficking and thereby elevation of calcium-activated potassium currents by intermittent burst pacing at the pulmonary vein-atrium interface provided an arrhythmogenic substrate for AF. 25 Interestingly, another report illustrated that genetic knockout of SK2 channels caused prolongation of action potential duration in atrial myocytes, and then AF. 26 Furthermore, another study also showed that pharmacological inhibition of SK channels resulted in prolongation of the atrial effective refractory period, thereby inhibiting reentry, and then AF prevention and termination.…”

Atrial fibrillation: the role of common and rare genetic variants

“…This APD shortening was inhibited by apamin, a blocker of the calcium-activated potassium channels. 31 This provides a possible basis of KCNN3 having a role in AF. The SNP rs3807989 is located close to the gene CAV1-encoding caveolin.…”

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

“…90,91 One important factor could be the shorter action potential duration (APD) of the PVs vs the atrium 84 due to larger delayed-rectifier K + currents and smaller inward Ca 2+ currents in the PV. 89,92,93 In addition, PVs demonstrate conduction abnormalities that promote reentry due to abrupt changes in fiber orientation as well as Na + channel inactivation by reduced resting potentials due to small I K1 . 84 Yet another study examined the impact of increasing atrial pressure on PV activation, finding that as LA pressure was increased above 10 cm H 2 O, the PV–LA junction became the source of dominant rotors.…”