Redox Regulation Of Ca 2+ Channels: From Orai To MCU

Abstract

Store-operated Ca2+ entry (SOCE) through the Ca2+release activated Ca2+ (CRAC) channels and mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) complex are collective signaling mechanisms responsible for many cellular functions. The CRAC channels are composed of three plasma membrane based proteins, known as Orai1, Orai2 and Orai3 and two ER based Ca2+ sensor proteins STIM1 and STIM2. The MCU complex includes proteins such as MCUa, EMRE, MICU1 and MICU2. We aim to understand the role of these proteins in immunity and in cancer. In particular, we want to unravel their regulation and functional interplay with the cellular redox system. We have shown that Orai1 and Orai2, but not Orai3 channels are inhibited by oxidation. The differential redox sensitivity of the Orai isoforms was attributed to a cysteine residue present in Orai1 and Orai2 but absent in Orai3. Moreover, we found that Orai channels form a feedback loop with the ROS-generating NADPH oxidase 2 (NOX2), thereby affecting monocyte function. In addition, we recently demonstrated that the assembly of the MCU complex is a redox-regulated process. Current studies indicate that redox regulation of Orai, STIM and MCU play a significant role in regulating innate immune responses and cancer pathobiology.