Wang Kaiqian, Nilsson Michelle, Angelini Marina, Olcese Riccardo, Elinder Fredrik, Pantazis Antonios
Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University; SE-581 85 Linköping, Sweden.
Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA.
bioRxiv. 2024 Sep 30:2024.09.27.615501. doi: 10.1101/2024.09.27.615501.
Depolarization-evoked opening of Ca2.1 (P/Q-type) Ca-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of Ca2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically tracked and physically characterized the structural dynamics of the four Ca2.1 voltage-sensor domains (VSDs). VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary -subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. Ca2.1 VSDs are differentially sensitive to voltage changes brief and long-lived. Specifically the voltage-dependent conformational changes of VSD-I are linked to synaptic release and plasticity.
去极化诱发的Ca2.1（P/Q型）钙通道开放触发神经递质释放，而电压依赖性失活（VDI）限制通道开放的可用性，这对突触可塑性有影响。Ca2.1对电压的反应机制尚不清楚。利用电压钳荧光测定法和动力学建模，我们通过光学跟踪并从物理上表征了四个Ca2.1电压传感器结构域（VSD）的结构动力学。VSD-I似乎直接驱动通道开放并在与VDI相关的两种功能模式之间转换。VSD-II显然对电压不敏感。VSD-III和VSD-IV感知更负的电压并经历与VDI不相关的电压依赖性转换。辅助β亚基调节VSD-I到孔的耦合以及VSD转换动力学。Ca2.1 VSD对短暂和持久的电压变化具有不同的敏感性。具体而言，VSD-I的电压依赖性构象变化与突触释放和可塑性相关。
