Constitutive calcium entry and cancer: updated views and insights

Tight control of basal cytosolic Ca²⁺ concentration is essential for cell survival and to fine-tune Ca²⁺-dependent cell functions. A way to control this basal cytosolic Ca²⁺ concentration is to regulate membrane Ca²⁺ channels including store-operated Ca²⁺ channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca²⁺ channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca²⁺ channels contributes to Ca²⁺ entry and the transient increase in cytosolic Ca²⁺ concentration involved in intracellular signaling. However, in various experimental conditions, Ca²⁺ entry and/or Ca²⁺ currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca²⁺ channels are already open/activated in basal condition, contributing therefore to constitutive Ca²⁺ entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities.