ABSTRACT

Voltage-gated calcium channels (VGCCs) are critical for Ca²⁺ influx into all types of excitable cells, but their exact function is still poorly understood. Recent reconstruction of homology models for all human VGCCs at atomic resolution provides the opportunity for a structure-based discussion of VGCC function and novel insights into the mechanisms underlying Ca²⁺ selective flux through these channels. In the present review, we use these data as a basis to examine the structure, function, and Zn²⁺-induced modulation of Ca_v2.3 VGCCs, which mediate native R-type currents and belong to the most enigmatic members of the family. Their unique sensitivity to Zn²⁺ and the existence of multiple mechanisms of Zn²⁺ action strongly argue for a role of these channels in the modulatory action of endogenous loosely bound Zn²⁺, pools of which have been detected in a number of neuronal, endocrine, and reproductive tissues. Following a description of the different mechanisms by which Zn²⁺ has been shown or is thought to alter the function of these channels, we discuss their potential (patho)physiological relevance, taking into account what is known about the magnitude and function of extracellular Zn²⁺ signals in different tissues. While still far from complete, the picture that emerges is one where Ca_v2.3 channel expression parallels the occurrence of loosely bound Zn²⁺ pools in different tissues and where these channels may serve to translate physiological Zn²⁺ signals into changes of electrical activity and/or intracellular Ca²⁺ levels.

摘要

电压门控钙通道（VGCC）对于Ca ²⁺流入所有类型的可兴奋细胞至关重要，但其确切功能仍知之甚少。最近在原子分辨率下重建所有人类VGCC的同源性模型，为基于结构的VGCC功能的讨论提供了机会，并为通过这些通道的Ca ²⁺选择性通量的潜在机制提供了新颖的见解。在本综述中，我们使用这些数据作为基础来研究Ca _v 2.3 VGCC的结构，功能和Zn ²⁺诱导的调节，这些介导天然R型电流并且属于该家族中最神秘的成员。它们对Zn ^2+的独特敏感性以及Zn多种机制的存在²⁺作用强烈主张这些通道在内源性松散结合的Zn ²⁺的调节作用中的作用，已在许多神经元，内分泌和生殖组织中检测到了这些池。在描述了显示或被认为会改变这些通道功能的锌²⁺的不同机制之后，我们讨论了它们潜在的（病理）生理相关性，同时考虑到有关细胞外锌的大小和功能的知识不同组织中的²⁺信号。尽管还不完整，但出现的情况是Ca _v 2.3通道表达与松散结合的Zn ²⁺的发生平行的在不同组织中的池中，这些通道可用于将生理Zn ²⁺信号转化为电活动和/或细胞内Ca ²⁺水平的变化。