1. A unique mechanism of inactivation gating of the Kv channel family member Kv7.1 and its modulation by PIP2 and calmodulin
- Author
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Maya Lipinsky, Adva Yeheskel, Yoav Paas, William Sam Tobelaim, Bernard Attali, Asher Peretz, Daniel Yakubovich, Joel A. Hirsch, Luba Simhaev, and Guy Lebel
- Subjects
Phosphatidylinositol 4,5-Diphosphate ,0303 health sciences ,Multidisciplinary ,Calmodulin ,biology ,Gating ,Kv channel ,03 medical and health sciences ,chemistry.chemical_compound ,Family member ,0302 clinical medicine ,chemistry ,Modulation ,Potassium Channels, Voltage-Gated ,Helix ,biology.protein ,Biophysics ,Family ,Phosphatidylinositol ,Linker ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Inactivation of voltage-gated K+ (Kv) channels mostly occurs by fast N-type or/and slow C-type mechanisms. Here, we characterized a unique mechanism of inactivation gating comprising two inactivation states in a member of the Kv channel superfamily, Kv7.1. Removal of external Ca2+ in wild-type Kv7.1 channels produced a large, voltage-dependent inactivation, which differed from N- or C-type mechanisms. Glu295 and Asp317 located, respectively, in the turret and pore entrance are involved in Ca2+ coordination, allowing Asp317 to form H-bonding with the pore helix Trp304, which stabilizes the selectivity filter and prevents inactivation. Phosphatidylinositol 4,5-bisphosphate (PIP2) and Ca2+-calmodulin prevented Kv7.1 inactivation triggered by Ca2+-free external solutions, where Ser182 at the S2-S3 linker relays the calmodulin signal from its inner boundary to the external pore to allow proper channel conduction. Thus, we revealed a unique mechanism of inactivation gating in Kv7.1, exquisitely controlled by external Ca2+ and allosterically coupled by internal PIP2 and Ca2+-calmodulin.
- Published
- 2020