Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

Abstract

A wide variety of cellular function depends on the dynamics of intracellular Ca(2+) signals. Especially for relatively slow and lasting processes such as gene expression, cell proliferation, and often migration, cells rely on the store-operated Ca(2+) entry (SOCE) pathway, which is particularly prominent in immune cells. SOCE is initiated by the sensor proteins (STIM1, STIM2) located within the endoplasmic reticulum (ER) registering the Ca(2+) concentration within the ER, and upon its depletion, cluster and trap Orai (Orai1-3) proteins located in the plasma membrane (PM) into ER-PM junctions. These regions become sites of highly selective Ca(2+) entry predominantly through Orai1-assembled channels, which, among other effector functions, is necessary for triggering NFAT translocation into the nucleus. What is less clear is how the spatial and temporal spread of intracellular Ca(2+) is shaped and regulated by differential expression of the individual SOCE genes and their splice variants, their heteromeric combinations and pre- and posttranslational modifications. This review focuses on principle mechanisms regulating expression, splicing, and targeting of Ca(2+) release-activated Ca(2+) (CRAC) channels.

The calcium–cancer signalling nexus

“…[H3] Activity remodelling Ca 2+ sensitive tumour promoting pathways could be effected even in the absence of altered expression of Ca 2+ channels and pumps by the array of mechanisms regulating the activity of calcium channels and pumps, including activity regulating proteins (e.g. STIM1), post-translational modifications, splicing and trafficking 36,[51][52][53][54][55] . For example the proteolytic cleavage of some Ca 2+ channels and pumps can yield either inactive or more active forms [56][57][58][59] , and in the case of proteolytic cleavage of CaV1.2 can produce a C-terminal fragment that acts as a transcription factor 54 .…”

The role of STIM proteins in neutrophil functions

“…) revealed that STIM‐mediated functions can be subject to complex physiological regulation, such as redox modulation and differential expression of protein variants (Bhardwaj et al . ; Niemeyer, ). The presence of two ORAI‐gating STIM isoforms allows a specialized regulation of physiological processes by a specific isoform.…”

“…STIM proteins are complex and multifaceted regulators of SOCE (Oh-Hora et al 2008;Soboloff et al 2012). The discoveries of functional STIM1 and STIM2 splice variants (Darbellay et al 2011;Miederer et al 2015;Rana et al 2015) and the identification of cysteine residues subject to oxidation (Hawkins et al 2010) revealed that STIM-mediated functions can be subject to complex physiological regulation, such as redox modulation and differential expression of protein variants (Bhardwaj et al 2016;Niemeyer, 2016). The presence of two ORAI-gating STIM isoforms allows a specialized regulation of physiological processes by a specific isoform.…”

The mitochondrial K-ATP channel opener diazoxide upregulates STIM1 and Orai1 via ROS and the MAPK pathway in adult rat cardiomyocytes

“…Furthermore, our ndings showing that NAC blocked both the translocation of this nuclear factor and upregulation of STIM1 and Orai1 suggest that these effects are related to ROS elevation. NFkB is a regulator of both STIM1 and Orai1 expression [26], and work done in mast cells and heterologous expression systems has demonstrated that binding of NFkB to speci c sites within the promoter regions of the STIM1 and Orai1 genes increases the transcription of their mRNAs [27].…”