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Department of Physiology and Biophysics, University at Buffalo, State University of New York, 124 Sherman Hall, Buffalo, NY 14214, USA
We conducted a kinetic analysis of the voltage dependence of macroscopic inactivation (
fast, slow), closed-state inactivation (closed,inact), recovery (rec), activation (act), and deactivation (deact) of Kv4.3 channels expressed alone in Xenopus oocytes and in the presence of the calcium-binding ancillary subunits KChIP2b and KChIP2d. We demonstrate that for all expression conditions, rec, closed,inact and fast are components of closed-state inactivation transitions. The values of closed,inact and fast monotonically merge from –30 to –20 mV while the values of closed,inact and rec approach each other from –60 to –50 mV. These data generate classic bell-shaped time-constant–potential curves. With the KChIPs, these curves are distinct from that of Kv4.3 expressed alone due to acceleration of rec and slowing of closed,inact and fast. Only at depolarized potentials where channels open is slow detectable suggesting that it represents an open-state inactivation mechanism. With increasing depolarization, KChIPs favour this open-state inactivation mechanism, supported by the observation of larger transient reopening currents upon membrane hyperpolarization compared to Kv4.3 expressed alone. We propose a Kv4.3 gating model wherein KChIP2 isoforms accelerate recovery, slow closed-state inactivation, and promote open-state inactivation. This model supports the observations that with KChIPs, closed-state inactivation transitions are [Ca2+]i-independent, while open-state inactivation is [Ca2+]i-dependent. The selective KChIP- and Ca2+-dependent modulation of Kv4.3 inactivation mechanisms predicted by this model provides a basis for dynamic modulation of the native cardiac transient outward current by intracellular Ca2+ fluxes during the action potential.
(Received 17 November 2003;
accepted after revision 9 January 2004;
first published online 14 January 2004)
Corresponding author D. L. Campbell: Department of Physiology and Biophysics, University at Buffalo, State University of New York, 124 Sherman Hall, Buffalo, NY 14214, USA. Email: dc25{at}buffalo.edu
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