Store-independent Orai1-mediated Ca Entry and Cancer

Ca channels play an important role in the development of different types of cancer, and considerable progress has been made to understand the pathophysiological mechanisms underlying the role of Ca influx in the development of different cancer hallmarks. Orai1 is among the most ubiquitous and multifunctional Ca channels. Orai1 mediates the highly Ca-selective Ca release-activated current (I) and participates in the less Ca-selective store-operated current (I), along with STIM1 or STIM1 and TRPC1, respectively. Furthermore, Orai1 contributes to a variety of store-independent Ca influx mechanisms, including the arachidonate-regulated Ca current, together with Orai3 and the plasma membrane resident pool of STIM1, as well as the constitutive Ca influx processes activated by the secretory pathway Ca-ATPase-2 (SPCA2) or supported by physical and functional interaction with the small conductance Ca-activated K channel 3 (SK3) or the voltage-dependent K10.1 channel. This review summarizes the current knowledge concerning the store-independent mechanisms of Ca influx activation through Orai1 channels and their role in the development of different cancer features.