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.
Highlights
STIM1 and Orai1 are sufficient for Ca2+ release-activated Ca2+ (CRAC) channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid- and/or endoplasmic reticulum (ER)-plasma membrane (PM) junctiondependent accessory proteins
In the following parts of the review, the focus is laid on the ER-PM contact sites, as this is the interface for the STIM1/Orai1 interplay
While a certain number of ER-PM contact of new contacts [74,140]. These events are often driven by the signaling steps of the elesites are already present in the resting state of the cell, Ca2+ store-depletion triggers the mentary unit of CRAC channels formed by STIM1 and Orai1, which accumulates in ERformation of new contacts [74,140]
Summary
Direct interactions between proteins and lipids or nonspecific changes in the physicochemical properties of the membrane, including curvature, fluidity, and thickness, can influence protein dynamics. The so-called mechanosensitive channels are sensitive to changes in membrane pressure and the resulting change in membrane curvature and thickness Examples of these types of ion channels include the bacterial large-conductance mechanosensitive channel (MscL) [21], piezo channels [22], and the potassium-selective TRAAK channel [23]. More recent reports concentrated on the role of signaling lipids, such as phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2, short: PIP2 ) or diacylglycerol (DAG) in the direct modulation of ion channels. Membrane and the second in the plasma membrane (PM) Before describing these two key proteins of the CRAC channel in detail, the section discusses the lipid composition and dynamics of the ER and the PM in the following
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