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, Linköping, Sweden.
Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Nat Commun. 2025 Apr 23;16(1):3815. doi: 10.1038/s41467-025-58884-2.
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 track and physically characterize the structural dynamics of the four Ca2.1 voltage-sensor domains (VSDs). The VSDs are differentially sensitive to voltage changes, both brief and long-lived. 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 β-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. Hence, the central role of Ca2.1 channels in synaptic release, and their contribution to plasticity, memory formation and learning, can arise from the voltage-dependent conformational changes of VSD-I.
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，我们通过光学追踪并从物理角度表征了四个Ca2.1电压传感器结构域（VSD）的结构动力学。这些VSD对短暂和长期的电压变化具有不同的敏感性。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与孔的耦合以及VSD转换动力学。因此，Ca2.1通道在突触释放中的核心作用及其对可塑性、记忆形成和学习的贡献，可能源于VSD-I的电压依赖性构象变化。
