Long-Chain Acylcarnitines Regulate the hERG Channel

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, K(IR)2.1 and K(v)7.1/minKchannels (channels responsible for I-KR, I-K1 and I-KS respectively). Experimental approach: HEK293 cells stably expressing hERG, K(IR)2.1 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 I-hERG amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on K(IR)2.1 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 to the changes in action potential duration thatprecede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency.