The Role of Lipids in CRAC Channel Function

Abstract

The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated by receptor-induced Ca2+ store depletion of the endoplasmic reticulum (ER) and consists of two transmembrane proteins, STIM1 and Orai1. STIM1 is anchored in the ER membrane and senses changes in the ER luminal Ca2+ concentration. Orai1 is the Ca2+-selective, pore-forming CRAC channel component located in the plasma membrane (PM). Ca2+ store-depletion of the ER triggers activation of STIM1 proteins, which subsequently leads to a conformational change and oligomerization of STIM1 and its coupling to as well as activation of Orai1 channels at the ER-PM contact sites. Although STIM1 and Orai1 are sufficient for CRAC channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid- and/or ER-PM junction-dependent accessory proteins. The underlying mechanisms for lipid-mediated CRAC channel modulation as well as the still open questions, are presented in this review.

CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development

“…Increasing evidence reveals that membrane proteins are localized in microdomains containing especially cholesterol, sphingolipids such as sphingomyelin, and glycosphingolipids [187]. These cholesterol-rich regions provide platforms required for membrane protein sorting and the assembly of signaling machinery, thus dictating protein-lipid and protein-protein interactions.…”

“…Additionally, perturbations to plasma membrane lipids affect other proteins that impact STIM1 and Orai1 expression and function. These include a variety of lipid-or ER-PM transition-dependent accessory proteins at the ER-PM contact sites [218], as we recently reviewed in detail [187]. Briefly, these include proteins situated in the ER that can establish direct or indirect interactions with the PM, namely, the Extended-synaptotagmins (E-Syts) with E-Syt 1-3 [219], GRAMD2A [220], and Anoctamin 8 (ANO8) [221].…”

Activation mechanisms and structural dynamics of STIM proteins

“…Store‐operated STIM1 activation triggers its association with Orai1 at ER–PM junctions (Zhou et al., 2010). Despite this interaction being sufficient for CRAC channels to open, their activity is modulated by a number of cellular components (Cao et al., 2015; Hogan, 2015; Maltan et al., 2022), such as directly by lipids (Balla, 2018; Bohorquez‐Hernandez et al., 2017; Carreras‐Sureda et al., 2021; Derler et al., 2016; Gwozdz et al., 2012; Pacheco et al., 2016), post‐translational modifications or indirectly by lipid‐dependent and ER–PM contact site‐dependent accessory proteins (Berlansky et al., 2021; Son et al., 2016), as outlined below. In addition, it is currently emerging that STIM expression is regulated by transcription factors, which, although not a direct regulatory mechanism, plays an important role in identifying developmental stages and physiological as well as pathophysiological conditions in which STIM proteins are essential.…”

“…Additional application of methyl‐β‐cyclodextrin (MβCD) did not further enhance STIM1 I364A mutant‐mediated Orai1 currents indicating that interference with the cholesterol‐binding motif is sufficient to increase STIM1‐mediated Ca 2+ entry via Orai1 (Pacheco et al., 2016). It is noteworthy that within the CRAC channel complex, not only STIM1 but also Orai1 contains a cholesterol binding motif (Derler et al., 2016; Maltan et al., 2022) the disruption of which results in increased Ca 2+ entry. Nevertheless, the effect of the removal of both binding sites is not additive, demonstrating that removal of one of the two binding sites is sufficient to mimic the effect of cholesterol removal from the membrane (Pacheco et al., 2016).…”