Deleting the accessory subunit KChIP2 results in loss of I to,f and increased I K,slow that maintains normal action potential configuration.

Background: Four voltage-gated potassium currents, I _to,f (K_V4.2), I _to,s (K_V1.4), I _K,slow (K_V1.5+K_V2.1), and I _SS (TASK1), govern murine ventricular repolarization. Although the accessory subunit KChIP2 influences I _to,f expression, in preliminary experiments we found that action potential duration (APD) is maintained in KChIP2 knockout mice. Objective: We tested the role of KChIP2 in regulating APD and studied the underlying ionic currents. Methods: We used microelectrode techniques, whole-cell patch clamp studies, and real-time polymerase chain reaction amplification to characterize ventricular repolarization and its determinants in wild-type and KChIP2^−/− mice. Results: Despite comparable baseline action potentials, APD was more markedly prolonged by 4-aminopyridine (4-AP) in KChIP2^−/− preparations. Peak K⁺ current densities were similar in wild-type and KChIP2^−/− cells (mean ± SEM I _P: 28.3 ± 2 (n = 27) vs. 29.2 ± 2 pA/pF (n = 24), respectively; P > .05). Heteropodatoxin-2 (HpTx-2, 1 μM) had no effect on current amplitude in KChIP2^−/− myocytes. The current fractions sensitive to 4-AP (50 μM and 1 mM) were larger in KChIP2^−/− than wild-type (P < .05). Real-time polymerase chain reaction showed absence of KChIP2 and increased K_V1.5 expression in KChIP2^−/− ventricular myocardium. Conclusion: KChIP2 deficiency eliminated HpTx-2-sensitive I _to,f, but had little impact on total APD, secondary to upregulation of 4-AP-sensitive I _K,slow in association with increased K_V1.5 expression. There is increased sensitivity to 4-AP-mediated APD prolongation in KChIP2^−/−. Thus, KChIP2 seems important for murine repolarization in circumstances of reduced repolarization reserve. [Copyright &y& Elsevier]