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Time- and Voltage-Dependent Components of Kv4.3 Inactivation

Shimin Wang ^* , Vladimir E. Bondarenko ^*, Yu-jie Qu ^*, Glenna C. L. Bett ^*, Michael J. Morales ^*, Randall L. Rasmusson ^* and Harold C. Strauss ^*

^* Department of Physiology and Biophysics, University at Buffalo, The State University of New York, School of Medicine and Biomedical Sciences, Buffalo, New York; and Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

Correspondence: Address reprint requests to Dr. Harold C. Strauss, Dept. of Physiology and Biophysics, University at Buffalo, The State University of New York, School of Medicine and Biomedical Sciences, 124 Sherman Hall, 3435 Main St., Buffalo, NY 14214. Tel.: 716-829-2738; Fax: 716-829-2344; E-mail: hstrauss{at}buffalo.edu.

Kv4.3 inactivation is a complex multiexponential process, which can occur from both closed and open states. The fast component of inactivation is modulated by the N-terminus, but the mechanisms mediating the other components of inactivation are controversial. We studied inactivation of Kv4.3 expressed in Xenopus laevis oocytes, using the two-electrode voltage-clamp technique. Inactivation during 2000 ms pulses at potentials positive to the activation threshold was described by three exponents (46 ± 3, 152 ± 13, and 930 ± 50 ms at +50 mV, n = 7) whereas closed-state inactivation (at potentials below threshold) was described by two exponents (1079 ± 119 and 3719 ± 307 ms at –40 mV, n = 9). The fast component of open-state inactivation was dominant at potentials positive to –20 mV. Negative to –30 mV, the intermediate and slow components dominated inactivation. Inactivation properties were dependent on pulse duration. Recovery from inactivation was strongly dependent on voltage and pulse duration. We developed an 11-state Markov model of Kv4.3 gating that incorporated a direct transition from the open-inactivated state to the closed-inactivated state. Simulations with this model reproduced open- and closed-state inactivation, isochronal inactivation relationships, and reopening currents. Our data suggest that inactivation can proceed primarily from the open state and that multiple inactivation components can be identified.

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