All KCNEs are expressed in the human heart at the transcript level. Compared to I(to) in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native I(to) channel.

Dipeptidyl-aminopeptidase-like protein 6 (DPPX) was recently shown in the brain to modulate the kinetics of transient A-type currents by accelerating inactivation and recovery from inactivation. Since the kinetics of human cardiac transient outward current (I to ) are not mimicked by coexpression of the α-subunit Kv4.3 with its known β-subunit KChIP2, we have tested the hypothesis that DPPX may serve as an additional β-subunit in the human heart. With quantitative real-time RT-PCR strong mRNA expression of DPPX was detected in human ventricles and was verified at the protein level in human but not in rat heart by a DPPX-specific antibody. Co-expression of DPPX with Kv4.3 in Chinese hamster ovary cells produced I to -like currents, but compared with expression of KChIP2a and Kv4.3, the time constant of inactivation was faster, the potential of half-maximum steady-state inactivation was more negative and recovery from inactivation was delayed. Co-expression of DPPX in addition to Kv4.3 and KChIP2a produced similar current kinetics as in human ventricular myocytes. We therefore propose that DPPX is an essential component of the native cardiac I to channel complex in human heart.

Background and purpose: This study was designed to establish the pathology-specific inhibitory effects of the I Kur /I to /I K,ACh blocker AVE0118 on atrium-selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF). Experimental approach: Outward K þ -currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole-cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting. Key results: Four components of outward K þ -currents and AF-specific alterations in their properties were identified. I to was smaller in cAF than in SR, and AVE0118 (10 mM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of I Kur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non-inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF-related constitutively active I K,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF. Conclusions and implications: In atrial myocytes of cAF patients, we detected reduced function of distinct I Kur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active I K,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.

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Background and purpose: The human cardiac transient outward potassium current (I to ) is believed to be composed of the pore-forming K V 4.3 a-subunit, coassembled with modulatory b-subunits as KChIP2, MiRP1 and DPP6 proteins. b-Subunits can alter the pharmacological response of I to ; therefore, we analysed the effects of flecainide on K V 4.3/KChIP2 channels coassembled with MiRP1 and/or DPP6 b-subunits. Experimental approach: Currents were recorded in Chinese hamster ovary cells stably expressing K V 4.3/KChIP2 channels, and transiently transfected with either MiRP1, DPP6 or both, using the whole-cell patch-clamp technique. Key results: In control conditions, K V 4.3/KChIP2/MiRP1 channels exhibited the slowest activation and inactivation kinetics and showed an 'overshoot' in the time course of recovery from inactivation. The midpoint values (V h ) of the activation and inactivation curves for K V 4.3/KChIP2/DPP6 and K V 4.3/KChIP2/MiRP1/DPP6 channels were E10 mV more negative than V h values for K V 4.3/KChIP2 and K V 4.3/KChIP2/MiRP1 channels. Flecainide (0.1-100 mM) produced a similar concentrationdependent blockade of total integrated current flow (IC 50 E10 mM) in all the channel complexes. However, the IC 50 values for peak current amplitude and inactivated channel block were significantly different. Flecainide shifted the V h values of both the activation and inactivation curves to more negative potentials and apparently accelerated inactivation kinetics in all channels. Moreover, flecainide slowed recovery from inactivation in all the channel complexes and suppressed the 'overshoot' in K V 4.3/ KChIP2/MiRP1 channels.