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(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.


CONCLUSIONS
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.
Thomsen
Morten B
MB
Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
Sosunov
Eugene A
EA
Anyukhovsky
Evgeny P
EP
Ozgen
Nazira
N
Boyden
Penelope A
PA
Rosen
Michael R
MR
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles; D066298:In Vitro Techniques; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051605:Kv Channel-Interacting Proteins; D024642:Potassium Channels, Voltage-Gated