Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel.
The Blavatnik Center for Drug Discovery, Tel Aviv University, Tel Aviv 69978, Israel.
Sci Adv. 2020 Dec 18;6(51). doi: 10.1126/sciadv.abd6922. Print 2020 Dec.
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 Ca in wild-type Kv7.1 channels produced a large, voltage-dependent inactivation, which differed from N- or C-type mechanisms. Glu and Asp located, respectively, in the turret and pore entrance are involved in Ca coordination, allowing Asp to form H-bonding with the pore helix Trp, which stabilizes the selectivity filter and prevents inactivation. Phosphatidylinositol 4,5-bisphosphate (PIP2) and Ca-calmodulin prevented Kv7.1 inactivation triggered by Ca-free external solutions, where Ser 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 Ca and allosterically coupled by internal PIP2 and Ca-calmodulin.
电压门控 K（Kv）通道的失活主要通过快速 N 型或/和缓慢 C 型机制发生。在这里，我们描述了 Kv 通道超家族成员失活门控的一种独特机制，该机制包含两个失活状态。在野生型 Kv7.1 通道中除去外部 Ca 会产生大的、电压依赖性的失活，这与 N 型或 C 型机制不同。位于炮塔和孔入口处的Glu 和 Asp 分别参与 Ca 配位，允许 Asp 与孔螺旋 Trp 形成氢键，从而稳定选择性过滤器并防止失活。磷脂酰肌醇 4,5-二磷酸（PIP2）和 Ca-钙调蛋白可防止由无 Ca 外部溶液触发的 Kv7.1 失活，其中 S2-S3 接头处的 Ser 将钙调蛋白信号从其内部边界传递到外部孔，以允许适当的通道传导。因此，我们揭示了 Kv7.1 中失活门控的一种独特机制，该机制由外部 Ca 精确控制，并通过内部 PIP2 和 Ca-钙调蛋白进行变构偶联。
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