Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UIJ5 (Rec)
 58,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We conducted a kinetic analysis of the voltage dependence of macroscopic inactivation (tau(fast), tau(slow)), closed-state inactivation (tau(closed,inact)), recovery (tau(rec)), activation (tau(act)), and deactivation (tau(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, tau(rec), tau(closed,inact) and tau(fast) are components of closed-state inactivation transitions. The values of tau(closed,inact) and tau(fast) monotonically merge from -30 to -20 mV while the values of tau(closed,inact) and tau(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 tau(rec) and slowing of tau(closed,inact) and tau(fast). Only at depolarized potentials where channels open is tau(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 [Ca(2+)](i)-independent, while open-state inactivation is [Ca(2+)](i)-dependent. The selective KChIP- and Ca(2+)-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 Ca(2+) fluxes during the action potential.
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PMID:Regulation of Kv4.3 voltage-dependent gating kinetics by KChIP2 isoforms. 1472 86

Kv4 pore-forming subunits are the principal constituents of the voltage-gated K+ channel underlying somatodendritic subthreshold A-type currents (I(SA)) in neurones. Two structurally distinct types of Kv4 channel modulators, Kv channel-interacting proteins (KChIPs) and dipeptidyl-peptidase-like proteins (DPLs: DPP6 or DPPX, DPP10 or DPPY), enhance surface expression and modify functional properties. Since KChIP and DPL distributions overlap in the brain, we investigated the potential coassembly of Kv4.2, KChIP3 and DPL proteins, and the contribution of DPLs to ternary complex properties. Immunoprecipitation results show that KChIP3 and DPP10 associate simultaneously with Kv4.2 proteins in rat brain as well as heterologously expressing Xenopus oocytes, indicating Kv4.2 + KChIP3 + DPP10 multiprotein complexes. Consistent with ternary complex formation, coexpression of Kv4.2, KChIP3 and DPP10 in oocytes and CHO cells results in current waveforms distinct from the arithmetic sum of Kv4.2 + KChIP3 and Kv4.2 + DPP10 currents. Furthermore, the Kv4.2 + KChIP3 + DPP10 channels recover from inactivation very rapidly (tau(rec) approximately 18-26 ms), closely matching that of native I(SA) and significantly faster than the recovery of Kv4.2 + KChIP3 or Kv4.2 + DPP10 channels. For comparison, identical triple coexpression experiments were performed using DPP6 variants. While most results are similar, the Kv4.2 + KChIP3 + DPP6 channels exhibit inactivation that slows with increasing membrane potential, resulting in inactivation slower than that of Kv4.2 + KChIP3 + DPP10 channels at positive voltages. In conclusion, the native neuronal subthreshold A-type channel is probably a macromolecular complex formed from Kv4 and a combination of both KChIP and DPL proteins, with the precise composition of channel alpha and auxiliary subunits underlying tissue and regional variability in I(SA) properties.
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PMID:Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties. 1612 12