| 19251214 |
Thomsen MB, Sosunov EA, Anyukhovsky EP, Ozgen N, Boyden PA, Rosen MR: Deleting the accessory subunit KChIP2 results in loss of I (to,f) and increased I (K,slow) that maintains normal action potential configuration. Heart Rhythm. 2009 Mar;6(3):370-7. Epub 2008 Nov 27.
BACKGROUND: Four voltage-gated potassium currents, I (to,f) (K (V) 4.2), I (to,s) (K (V) 1.4), I (K,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,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 microM) had no effect on current amplitude in KChIP2 (-/-) myocytes. The current fractions sensitive to 4-AP (50 microM and 1 mM) were larger in KChIP2 (-/-) than wild-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,f), but had little impact on total APD, secondary to upregulation of 4-AP-sensitive I (K,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. |
16(0,0,1,11) |