Ca_v2.3 channel function and Zn²⁺-induced modulation: potential mechanisms and (patho)physiological relevance

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.