STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane.

Abstract

Recent studies have indicated a critical role for STIM (stromal interacting molecule) proteins in the regulation of the store-operated mode of receptor-activated Ca2+ entry. Current models emphasize the role of STIM located in the endoplasmic reticulum membrane, where a Ca2+-binding EF-hand domain within the N-terminal of the protein lies within the lumen and is thought to represent the sensor for the depletion of intracellular Ca2+ stores. Dissociation of Ca2+ from this domain induces the aggregation of STIM to regions of the ER immediately adjacent to the plasma membrane where it acts to regulate the activity of store-operated Ca2+ channels. However, the possible effects of STIM on other modes of receptor-activated Ca2+ entry have not been examined. Here we show that STIM1 also regulates the arachidonic-acid-regulated Ca2+-selective (ARC) channels - receptor-activated Ca2+ entry channels whose activation is entirely independent of store depletion. Regulation of the ARC channels by STIM1 does not involve dissociation of Ca2+ from the EF-hand, or any translocation of STIM1. Instead, a critical role of STIM1 resident in the plasma membrane is indicated. Thus, exposure of intact cells to an antibody targeting the extracellular N-terminal domain of STIM1 inhibits ARC channel activity without significantly affecting the store-operated channels. A similar specific inhibition of the ARC channels is seen in cells expressing a STIM1 construct in which the N-linked glycosylation sites essential for the constitutive cell surface expression of STIM1, were mutated. We conclude that, in contrast to store-operated channels, regulation of ARC channels by STIM1 depends exclusively on the pool of STIM1 constitutively residing in the plasma membrane. These data demonstrate that STIM1 is a more universal regulator of Ca2+ entry pathways than previously thought, and appears to have multiple modes of action.

• Authors: Olivier Mignen, Jill L Thompson, Trevor J Shuttleworth
• Journal: The Journal of physiology (J Physiol) Vol. 579 Issue Pt 3 Pg. 703-15 (Mar 15 2007) ISSN: 0022-3751 [Print] England
• PMID: 17158173 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• Membrane Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• STIM1 protein, human
• Stromal Interaction Molecule 1
• Arachidonic Acid
• Calcium

Topics

• Arachidonic Acid (pharmacology)
• Calcium (metabolism)
• Calcium Channels (genetics, physiology)
• Cell Membrane (metabolism)
• Cells, Cultured
• Gene Expression (physiology)
• Humans
• Kidney (cytology)
• Membrane Potentials (drug effects, physiology)
• Membrane Proteins (genetics, metabolism, physiology)
• Mutagenesis (physiology)
• Neoplasm Proteins (genetics, physiology)
• Patch-Clamp Techniques
• Protein Transport (physiology)
• RNA, Small Interfering
• Stromal Interaction Molecule 1