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- W4319915983 abstract "The Kv2.1 delayed-rectifier K+ channel is one of the most abundant ion channels in the mammalian brain, where it is critical for neuronal activity, with mutations in humans causing epileptic encephalopathies. Kv2.1 opens slowly in response to membrane depolarization and slowly inactivates on the timescale of seconds. Slow inactivation in Kv2.1 is not sensitive to several manipulations that strongly influence C-type inactivation in Kv1 channels, including raising the concentration of external K+, external blockers such as tetraethylammonium (TEA) and mutations in the external pore near the ion selectivity filter. We solved the cryo-EM structure of Kv2.1 at 2.9-Å resolution, which reveals that the protein adopts an overall fold that is similar to Kv1 channels. Mutations causing epileptic encephalopathies are distributed throughout the structure of the transmembrane region of Kv2.1, producing distinct alterations in voltage-dependent activation. One particularly interesting epileptic encephalopathy mutant of a Phe to Leu near the internal end of the S6 pore-lining helix, rendered the channel effectively non-conducting; gating currents arising from activation of the voltage sensors could be measured without any evidence of ion conduction. From the cryo-EM structure, we identified a cluster of three Leu residues that interact intimately with the Phe, and when mutated to Ala remained conducting but with greatly accelerated (10-100-fold) slow inactivation. Experiments using internal TEA to detect opening of the internal gate in the non-conducting mutant of Kv2.1 suggest that the internal gate remains closed. From these and other findings, we propose that slow inactivation in Kv2.1 involves electromechanical coupling between the voltage sensors and pore, with reclosure of the internal gate occurring while the voltage sensors remain activated." @default.
- W4319915983 created "2023-02-11" @default.
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- W4319915983 date "2023-02-01" @default.
- W4319915983 modified "2023-09-28" @default.
- W4319915983 title "Cryo-EM structure of the mammalian Kv2.1 channel and epileptic encephalopathy mutations provide insight into electromechanical coupling and slow inactivation" @default.
- W4319915983 doi "https://doi.org/10.1016/j.bpj.2022.11.2109" @default.
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