Reciprocal Relationship between Ca²⁺ Signaling and Ca²⁺-Gated Ion Channels as a Potential Target for Drug Discovery

Abstract

Cellular Ca²⁺ signaling functions as one of the most common second messengers of various signal transduction pathways in cells and mediates a number of physiological roles in a cell-type dependent manner. Ca²⁺ signaling also regulates more general and fundamental cellular activities, including cell proliferation and apoptosis. Among ion channels, Ca²⁺-permeable channels in the plasma membrane as well as endo- and sarcoplasmic reticulum membranes play important roles in Ca²⁺ signaling by directly contributing to the influx of Ca²⁺ from extracellular spaces or its release from storage sites, respectively. Furthermore, Ca²⁺-gated ion channels in the plasma membrane often crosstalk reciprocally with Ca²⁺ signals and are central to the regulation of cellular functions. This review focuses on the physiological and pharmacological impact of i) Ca²⁺-gated ion channels as an apparatus for the conversion of cellular Ca²⁺ signals to intercellularly propagative electrical signals and ii) the opposite feedback regulation of Ca²⁺ signaling by Ca²⁺-gated ion channel activities in excitable and non-excitable cells.