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首页> 外文期刊>Journal of cellular physiology. >STAC3 determines the slow activation kinetics of CaV1.1 currents and inhibits its voltage‐dependent inactivation
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STAC3 determines the slow activation kinetics of CaV1.1 currents and inhibits its voltage‐dependent inactivation

机译：STAC3 确定 CaV1.1 电流的缓慢活化动力学并抑制其电压依赖性失活

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Abstract The skeletal muscle CaV1.1 channel functions as the voltage‐sensor of excitation?contraction (EC) coupling. Recently, the adaptor protein STAC3 was found to be essential for both CaV1.1 functional expression and EC coupling. Interestingly, STAC proteins were also reported to inhibit calcium‐dependent inactivation (CDI) of L‐type?calcium channels (LTCC), an important negative feedback mechanism in calcium signaling. The same could not be demonstrated for CaV1.1, as STAC3 is required for its functional expression. However, upon strong membrane depolarization, CaV1.1 conducts calcium currents characterized by very slow kinetics of activation and inactivation. Therefore, we hypothesized that the negligible inactivation observed in CaV1.1 currents reflects the inhibitory effect of STAC3. Here, we inserted a triple mutation in the linker region of STAC3 (ETLAAA), as the analogous mutation abolished the inhibitory effect of STAC2 on CDI of CaV1.3 currents. When coexpressed in CaV1.1/STAC3 double knockout myotubes, the mutant STAC3‐ETLAAA failed to colocalize with CaV1.1 in the sarcoplasmic reticulum/membrane junctions. However, combined patch‐clamp and calcium recording experiments revealed that STAC3‐ETLAAA supports CaV1.1 functional expression and EC coupling, although at a reduced extent compared to wild‐type STAC3. Importantly, STAC3‐ETLAAA coexpression dramatically accelerated the kinetics of activation and inactivation of CaV1.1 currents, suggesting that STAC3 determines the slow CaV1.1 currents kinetics. To examine if STAC3 specifically inhibits the CDI of CaV1.1 currents, we performed patch‐clamp recordings using calcium and barium as charge carriers in HEK cells. While CaV1.1 displayed negligible CDI with STAC3, this did not increase in the presence of STAC3‐ETLAAA. On the contrary, our data demonstrate that STAC3 specifically inhibits the voltage‐dependent inactivation (VDI) of CaV1.1 currents. Altogether, these results designate STAC3 as a crucial determinant for the slow activation kinetics of CaV1.1 currents and implicate STAC proteins as modulators of both components of inactivation of LTCC.
机译：摘要骨骼肌CaV1.1通道函数的电压检测传感器兴奋吗?适配器蛋白质STAC3被发现基本都CaV1.1函数表达式和EC耦合。也报道了抑制钙量依赖失活(CDI) L列车类型?高瓦斯),一个重要的负反馈机制在钙信号。CaV1.1演示,STAC3所需其函数表达式。膜去极化,CaV1.1进行钙电流的特点是非常缓慢的动力学激活和失活。假设微不足道的失活反映了在CaV1.1电流STAC3的抑制作用。突变STAC3链接器区域的三倍(ETLAAA),类似的变异废除了抑制作用的STAC2 CaV1.3 CDI电流。淘汰赛肌管,变异STAC3 ETLAAA应承担的失败了与CaV1.1 colocalize肌质网/膜连接。片夹和钙记录实验透露,STAC3 ETLAAA CaV1.1支持函数表达式和EC耦合,虽然在一个比STAC3型野生量减少程度。重要的是,STAC3必经ETLAAA coexpression大大加速了动力学CaV1.1电流的激活和失活,这表明STAC3决定CaV1.1缓慢水流动力学。特别是抑制的CDI CaV1.1电流,我们执行补丁夹使用钙录音在HEK细胞和钡电荷载体。与STAC3 CDI CaV1.1显示可以忽略不计,这没有增加STAC3 ETLAAA应承担的存在。相反,我们的数据表明STAC3特别是抑制电压的依赖失活(VDI) CaV1.1电流。总之,这些结果指定STAC3作为缓慢激活的关键决定因素动力学CaV1.1水流和涉及STAC蛋白质作为调节器的两个组成部分确立的失活。

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