Deleting the accessory subunit KChIP2 results in loss of Ito,f and increased IK,slow that maintains normal action potential configuration

BACKGROUND: Four vottage-gated potassium currents, I-to,I-f (K(V)4.2), I-to,I-s (K(V)1.4), I-K,I-slow (K(V)1.5+K(V)2.1), and I-ss (TASK1), govern murine ventricular repolarization. Although the accessory subunit KChIP2 influences I-to,I-f expression, in preliminary experiments we found that action potential duration (APD) is maintained in KChIP2 knockout mice. OBJECTIVE: We tested the rote 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 witd-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 mu M) had no effect on current amplitude in KChIP2(-/-) myocytes. The current fractions sensitive to 4-AP (50 mu M and 1 mM) were larger in KChIP2(-/-) than witd-type (P < .05). Real-time polymerase chain reaction showed absence of KChIP2 and increased K(V)1.5 expression in KChIP2(-/-) ventricular myocardium. CONCLUSION: KChIP2 deficiency eliminated HpTx-2-sensitive I-to,I-f, but had little impact on total APD, secondary to upreguLation of 4-AP-sensitive I-K,I-slow in association with increased K(V)1.5 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.