Long-chain acylcarnitines regulate the herg channel

Abstract

Background and purpose: In some pathological conditions carnitine concentration is high while in othersitis low.In bothcases,cardiac arrhythmiascan occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmiasthrough modulation of ionic currents. We studied the effects of acyl-CARs on hERG, KIR2.1 and Kv7.1/minKchannels (channels responsible for IKR, IK1 and IKS respectively). Experimental approach: HEK293 cells stably expressing hERG, KIR2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. Forstudies onhERG, C16 and C18:1 free fatty acid were also used. Key results: Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of IhERG amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on KIR2.1 or Kv7.1/minK currents.Computer simulations of these effects wereconsistent with changes in action potential profile. Conclusions and applications: Extracellular LCAC tonically regulates IhERG amplitude and kineticsunder physiological conditions. This modulation maycontribute tothe changes in action potential duration thatprecede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency. © 2012 Ferro et al.