More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins.

Sascha Berlansky,Irene Frischauf,Christina Humer,Matthias Sallinger

doi:10.3390/ijms22010471

Abstract

The calcium-release-activated calcium (CRAC) channel, activated by the release of Ca2+ from the endoplasmic reticulum (ER), is critical for Ca2+ homeostasis and active signal transduction in a plethora of cell types. Spurred by the long-sought decryption of the molecular nature of the CRAC channel, considerable scientific effort has been devoted to gaining insights into functional and structural mechanisms underlying this signalling cascade. Key players in CRAC channel function are the Stromal interaction molecule 1 (STIM1) and Orai1. STIM1 proteins span through the membrane of the ER, are competent in sensing luminal Ca2+ concentration, and in turn, are responsible for relaying the signal of Ca2+ store-depletion to pore-forming Orai1 proteins in the plasma membrane. A direct interaction of STIM1 and Orai1 allows for the re-entry of Ca2+ from the extracellular space. Although much is already known about the structure, function, and interaction of STIM1 and Orai1, there is growing evidence that CRAC under physiological conditions is dependent on additional proteins to function properly. Several auxiliary proteins have been shown to regulate CRAC channel activity by means of direct interactions with STIM1 and/or Orai1, promoting or hindering Ca2+ influx in a mechanistically diverse manner. Various proteins have also been identified to exert a modulatory role on the CRAC signalling cascade although inherently lacking an affinity for both STIM1 and Orai1. Apart from ubiquitously expressed representatives, a subset of such regulatory mechanisms seems to allow for a cell-type-specific control of CRAC channel function, considering the rather restricted expression patterns of the specific proteins. Given the high functional and clinical relevance of both generic and cell-type-specific interacting networks, the following review shall provide a comprehensive summary of regulators of the multilayered CRAC channel signalling cascade. It also includes proteins expressed in a narrow spectrum of cells and tissues that are often disregarded in other reviews of similar topics.

Highlights

Apart from proteins involved in cell surface expression of Orai1, endocytosis, and turnover, endoplasmic reticulum (ER)-sculpturing proteins and these involved in the establishment/maintenance of ER-plasma membrane (PM) junctions are included as well as others regulated by Stromal interaction molecule 1 (STIM1)/Orai1 or those involved in downstream responses, as will be treated in upcoming sections
Co-immunoprecipitation analysis indicated interactions between Orai1 and SPCA2C that correlated with the patterns of STIM1 expression, its modulation of SOCE was intriguingly reported to be independent of this association and to occur in an Orai1-independent manner [36]
Contrasting SPCA2-dependent incorporation into the plasma membrane, calcium-release-activated calcium (CRAC) channels are withdrawn from the cell surface in the course of meiosis to hinder store-operated currents from activating

Summary

Introduction

While folded towards the ER-membrane upon rest, the activation of STIM1 includes an extension of its C-terminus vital to allow for interactions with cytosolic domains of pore-forming Orai proteins. There, they either function in a store-operated and STIM-regulated manner if associated with members of the canonical type of transient receptor potential proteins (TRPC) or, upon forming pentameric assemblies with the Orai isoform, give rise to arachidonate-regulated Ca2+ (ARC) channels The latter are functionally detached from internal Ca2+ stores and modulated by a fraction of STIM1 proteins resident in the plasma membrane rather than the ER [19]. Given that interacting proteins and indirect regulators hold vital roles in CRAC channel function but are often left in disregard in the rather STIM1/Orai1centered research field, the following review focuses on a compacted recapitulation of so far published modulators of STIM1 and/or Orai

Protein Trafficking and Dynamics

Positive Modulators of SOCE

Negative Modulators of SOCE