Our results demonstrated that in SR there are intra-atrial heterogeneities in the repolarizing currents. CAF decreases I(to1) and I(Kur) differentially in each atrium and increases I(Ks) in both atria, an effect that further promotes re-entry.

Both increase and decrease of cardiac inward rectifier current (I K1 ) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I K1 (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I Kir2.1 ) and I K1 recorded in ventricular myocytes. Flecainide increases outward I Kir2.1 generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I Kir2.2 and I Kir2.3 , because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.T he cardiac inwardly rectifying K + current (I K1 ) stabilizes resting membrane potential (RMP) close to the reversal potential of K + (E K ) and shapes the final repolarization phase of the action potential (AP) (1). Three inwardly rectifying channels (Kir2.1, Kir2.2, and Kir2.3) contribute to I K1 in the human heart assembled as homo-and/or heterotetramers (2). Experimental data suggest that in humans, Kir2.1 is the major isoform underlying ventricular I K1 , whereas its relative contribution to atrial I K1 seems to be lower (3). The strong inward rectification of Kir2.x channels, i.e., the preferential conduction of inward compared with outward current, depends on the binding of intracellular Mg 2+ and polyamines to the cytoplasmic pore and to the inner vestibule of the channel (4).Gain-and loss-of-function mutations in the gene that encodes Kir2.1 (KCNJ2) have been reported, and both the I K1 increase and decrease produced by these mutations are associated with severe ventricular arrhythmias (1). Furthermore, experimental data showed that as the amplitude of the outward component of the I K1 increases, the frequency of the fast and stable reentry of spiral waves (rotors) increases. Indeed, the importance of I K1 in the establishment of rotors and ventricular fibrillation dynamics has been shown (5).Flecainide is a class I antiarrhythmic drug that, besides its Na + channel-blocking properties, exhibits class III antiarrhythmic effects [i.e., prolongs AP duration (APD) and refractoriness] at the atrial but not at the ventricular le...

The present results demonstrate that CAF increases the effects of β1-Adrenoceptor stimulation on repolarizing currents by means of a chamber-specific up-regulation of the receptors. This, together with the ion channel derangements produced by CAF, could contribute to the long-term stabilization of the arrhythmia by shortening the AP duration.

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IntroductionWe functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na+ channels (Nav1.5) found in a proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry the mutation and showed a Brugada syndrome with an incomplete and variable expression. The mutation (p.D1816VfsX7) resulted in a severe truncation (201 residues) of the Nav1.5 C-terminus. Methods and ResultsWild-type (WT) and mutated Nav1.5 channels together with hNavβ1 were expressed in CHO cells and currents were recorded at room temperature using the whole-cell patch-clamp. Expression of p.D1816VfsX7 alone resulted in a marked reduction (≈90%) in peak Na+ current density compared with WT channels. Peak current density generated by p.D1816VfsX7+WT was ≈50% of that generated by WT channels. p.D1816VfsX7 positively shifted activation and inactivation curves, leading to a significant reduction of the window current. The mutation accelerated current activation and reactivation kinetics and increased the fraction of channels developing slow inactivation with prolonged depolarizations. However, late INa was not modified by the mutation. p.D1816VfsX7 produced a marked reduction of channel trafficking toward the membrane that was not restored by decreasing incubation temperature during cell culture or by incubation with 300 μM mexiletine and 5 mM 4-phenylbutirate. ConclusionDespite a severe truncation of the C-terminus, the resulting mutated channels generate currents, albeit with reduced amplitude and altered biophysical properties, confirming the key role of the C-terminal domain in the expression and function of the cardiac Na+ channel.

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