Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases.

Valentina Tedeschi,Antonio Vinciguerra,Daniele La Russa,Diana Amantea,Cristina Franco,Agnese Secondo

doi:10.3390/cells10102518

Abstract

Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L-type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.

Highlights

Stromal interacting molecule 1 (STIM1), a single transmembrane-spanning domain protein mainly residing in the endoplasmic reticulum (ER), is the unique ER Ca2+ sensor deputed to ER Ca2+ refilling [1]
Several other STIM1 targets located in different cell compartments may serve to handle intracellular calcium concentration including plasmalemmal and intracellular channels (e.g., transient receptor potential channel 1 (TRPC1), L-type voltage-dependent Ca2+ channels and TRPML1), and pumps (e.g., plasma membrane Ca2+-ATPase (PMCA) and sarco/endoplasmic reticulum Ca2+ ATPase (SERCA))
Through the modulation of STIM1 activity and interaction, many adaptors indirectly intervene in intracellular calcium homeostasis regulation

Summary

Introduction

Stromal interacting molecule 1 (STIM1), a single transmembrane-spanning domain protein mainly residing in the endoplasmic reticulum (ER), is the unique ER Ca2+ sensor deputed to ER Ca2+ refilling [1]. A number of proteins have been proposed to interact with STIM1, which are located both in the plasma membrane and at different intracellular levels Some of these proteins may be considered as molecular partners of STIM1 and include Orai, TRPC channels, L-type voltage-dependent Ca2+ channels, plasma membrane Ca2+-ATPase (PMCA), exportin, transportin, SERCA2, SERCA3, etc. POST prevents PMCA4 from STIM1-mediated inhibition, determining the proper coupling of PMCA4 to Orai1 This promotes Ca2+ entry mechanism and NFAT activation in Jurkat T cells [53]. Orai co-localizes with STIM1 and L-type VGCC at ER-PM junctions after store depletion, suggesting the involvement of the plasma membrane component of SOCE in the modulation of L-type VGCC. This may occur through a bidirectional interplay between the two organelles, both able to refill with Ca2+ ions in both physiological and pathological conditions [69]

Nuclear Proteins

STIM1 Scaffold Proteins

Molecular Modulators of STIM1

STIM1 Partners in Neurodegenerative Diseases

Ischemic Injury

Conclusions