Oxysterols and calcium signal transduction

Ionised calcium (Ca ²⁺) is a key second messenger, regulating almost every cellular process from cell death to muscle contraction. Cytosolic levels of this ion can be increased via gating of channel proteins located in the plasma membrane, endoplasmic reticulum and other membrane-delimited organelles. Ca ²⁺ can be removed from cells by extrusion across the plasma membrane, uptake into organelles and buffering by anionic components. Ca ²⁺ channels and extrusion mechanisms work in concert to generate diverse spatiotemporal patterns of this second messenger, the distinct profiles of which determine different cellular outcomes. Increases in cytoplasmic Ca ²⁺ concentration are one of the most rapid cellular responses upon exposure to certain oxysterol congeners or to oxidised low-density lipoprotein, occurring within seconds of addition and preceding increases in levels of reactive oxygen species, or changes in gene expression. Furthermore, exposure of cells to oxysterols for periods of hours to days modulates Ca ²⁺ signal transduction, with these longer-term alterations in cellular Ca ²⁺ homeostasis potentially underlying pathological events within atherosclerotic lesions, such as hyporeactivity to vasoconstrictors observed in vascular smooth muscle, or ER stress-induced cell death in macrophages. Despite their candidate roles in physiology and disease, little is known about the molecular mechanisms that couple changes in oxysterol concentrations to alterations in Ca ²⁺ signalling. This review examines the ways in which oxysterols could influence Ca ²⁺ signal transduction and the potential roles of this in health and disease.