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J Gen Physiol 2009 Feb 01;1332:205-24. doi: 10.1085/jgp.200810073.
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Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels.

Barghaan J , Bähring R .

Voltage-gated potassium channels related to the Shal gene of Drosophila (Kv4 channels) mediate a subthreshold-activating current (I(SA)) that controls dendritic excitation and the backpropagation of action potentials in neurons. Kv4 channels also exhibit a prominent low voltage-induced closed-state inactivation, but the underlying molecular mechanism is poorly understood. Here, we examined a structural model in which dynamic coupling between the voltage sensors and the cytoplasmic gate underlies inactivation in Kv4.2 channels. We performed an alanine-scanning mutagenesis in the S4-S5 linker, the initial part of S5, and the distal part of S6 and functionally characterized the mutants under two-electrode voltage clamp in Xenopus oocytes. In a large fraction of the mutants (>80%) normal channel function was preserved, but the mutations influenced the likelihood of the channel to enter the closed-inactivated state. Depending on the site of mutation, low-voltage inactivation kinetics were slowed or accelerated, and the voltage dependence of steady-state inactivation was shifted positive or negative. Still, in some mutants these inactivation parameters remained unaffected. Double mutant cycle analysis based on kinetic and steady-state parameters of low-voltage inactivation revealed that residues known to be critical for voltage-dependent gate opening, including Glu 323 and Val 404, are also critical for Kv4.2 closed-state inactivation. Selective redox modulation of corresponding double-cysteine mutants supported the idea that these residues are involved in a dynamic coupling, which mediates both transient activation and closed-state inactivation in Kv4.2 channels.

PubMed ID: 19171772
PMC ID: PMC2638201
Article link: J Gen Physiol

Species referenced: Xenopus laevis
Genes referenced: dpp6 kcna2 kcnb1 kcnc1 kcnc3 kcnd2 kcnip2 tbx2

Article Images: [+] show captions
References [+] :
Barghaan, Role of N-terminal domain and accessory subunits in controlling deactivation-inactivation coupling of Kv4.2 channels. 2008, Pubmed