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Capacitative calcium entry

James W. Putney, Jr.

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health Department of Health and Human Services, Research Triangle Park, NC 27709

Correspondence to James W. Putney, Jr: putney{at}niehs.nih.gov

Abstract

A long-standing mystery in the cell biology of calcium channel regulation is the nature of the signal linking intracellular calcium stores to plasma membrane capacitative calcium entry channels. An RNAi-based screen of selected Drosophila genes has revealed that a calcium-binding protein, stromal interaction molecule (STIM), plays an essential role in the activation of these channels and may be the long sought sensor of calcium store content.

Abbreviations used in this paper: CIF, calcium influx factor; IP₃, inositol 1,4,5-trisphosphate; SAM, sterile motif; STIM, stromal interaction molecule.

Virtually all cell types depend in some manner upon the generation of cytoplasmic Ca²⁺ signals to regulate cell function, or to trigger specific responses. Usually, these signals involve some combination of release of Ca²⁺ from intracellular stores and influx of Ca²⁺ across the plasma membrane. The release of Ca²⁺ from intracellular stores is often signaled by the messenger inositol 1,4,5-trisphosphate (IP₃), and additionally by a process of calcium-induced calcium release (Berridge, 1997). The influx of Ca²⁺ across the plasma membrane can be signaled by a variety of mechanisms (Barritt, 1999). In most cell types, depletion of intracellular Ca²⁺ stores signals the activation of capacitative calcium entry, occurring through store-operated calcium channels (Putney, 1997). However, the nature of the store-operated channels as well as the mechanism linking their activation to the Ca²⁺ content of intracellular stores has remained a mystery. Now, Roos et al. (2005) provide exciting new information on a key player in this elusive mechanism (on page 435 of this issue).

The authors used an RNAi screen in Drosophila S2 cells using thapsigargin-activated Ca²⁺ entry as a marker for store-operated channels. They screened 170 genes, including a number of transient receptor potential genes, other known calcium permeable channel genes, and a number of genes for potentially interacting signaling molecules. One gene gave a substantially reduced Ca²⁺ entry, coding for the protein stromal interaction molecule (STIM). Direct measurement of the store-operated current in S2 cells confirmed that the Ca²⁺-release–activated Ca²⁺ current (I_crac) was essentially null in STIM knockdown S2 cells. There are two homologues of STIM in mammalian cells, STIM1 and STIM2, both of which appear to be distributed ubiquitously (Williams et al., 2001). Knockdown of STIM1 by RNAi substantially reduced I_crac in Jurkat T cells, and store-operated Ca²⁺ entry in HEK293 epithelial cells and SH-SY5Y neuroblastoma cells. However, knockdown of the closely related STIM2 had no effect.

These results make a strong case for an essential role of STIM (Drosophila) and STIM1 (mammals) in the mechanism of activation of store-operated channels. It is unlikely that STIM1 is the store-operated channel itself. It has no channel-like sequence, and overexpression of the protein only modestly enhanced Ca²⁺ entry. The obvious next question, then, is: what role does STIM1 play? Clues to the action of STIM1 may come from its domain structure and cellular localization. Apparently, the protein is located both on the plasma and intracellular membranes (Manji et al., 2000), presumably the ER. The protein sequence suggests that it spans the membrane once, with its NH₂ terminus oriented toward the lumen of the ER or the extracellular space (Fig. 1). The NH₂ terminus contains an EF-hand domain, and thus, as Roos et al. (2005) point out, the protein could function as the long-sought Ca²⁺ sensor in the ER. The protein also contains protein–protein interaction domains, notably coiled-coiled domains in the cytoplasm and a sterile motif (SAM) in the ER (or extracellular space), both near the predicted transmembrane domain (Fig. 1). STIM1 can oligomerize and Roos et al. (2005) speculate that the protein in the ER and plasma membrane could interact bridging the two. This idea is reminiscent of the conformational coupling hypothesis (Irvine, 1990; Berridge, 1995), according to which ER stores communicate with the plasma membrane by means of protein–protein interactions. Finally, STIM1 has an extended COOH terminus that contains a proline/serine-rich domain and a lysine-rich domain. However, most of the sequence downstream of the coiled-coil domain is missing in Drosophila STIM, indicating that it is not of prime importance in store-operated Ca²⁺ entry.

View larger version (38K): [in this window] [in a new window]   Figure 1. STIM1 and SOC activation. In this example, cell activation begins with an agonist binding to a surface membrane receptor (R), coupled to PLC through a G-protein (G) mechanism. PLC activation leads to the production of IP3, which in turn activates the IP3 receptor (IP3R) causing release of Ca2+ from a critical compartment of the ER. The fall in ER Ca2+ then signals to plasma membrane store-operated channels (SOC) through a mechanism that involves STIM1 in the ER, plasma membrane, or both. The structure of STIM1 includes an EF hand and SAM domain NH2-terminal to a single transmembrane (TM) domain; these domains would face the lumen of the ER and extracellular space, and the EF hand in particular may be involved in sensing ER Ca2+ levels, or in Ca2+ regulation at the plasma membrane. COOH-terminal to the TM domain are two coiled-coil (CC) domains, and a serine/proline-rich (S/P Rich) and lysine (K Rich) domain. The EF hand domain is shown in red on the signaling diagram as well as the domain map to indicate the presumed orientation of the protein across ER and plasma membranes.

The details of the precise action of STIM1 in capacitative calcium entry are far from clear at present. But it is the early days. The discovery of a key player in this ubiquitous signaling pathway no doubt opens the way for intriguing new disclosures in the very near future.

Submitted: 29 March 2005

Accepted: 4 April 2005

References

Barritt, G.J. 1999. Receptor-activated Ca²⁺ inflow in animal cells: a variety of pathways tailored to meet different intracellular Ca²⁺ signalling requirements. Biochem. J. 337:153–169.

Berridge, M.J. 1995. Capacitative calcium entry. Biochem. J. 312:1–11.

Berridge, M.J. 1997. Elementary and global aspects of calcium signalling. J. Physiol. 499:291–306.[Free Full Text]

Irvine, R.F. 1990. "Quantal" Ca²⁺ release and the control of Ca²⁺ entry by inositol phosphates—a possible mechanism. FEBS Lett. 263:5–9.[CrossRef][Medline]

Kim, H.Y., D. Thomas, and M.R. Hanley. 1995. Chromatographic resolution of an intracellular calcium influx factor from thapsigargin-activated Jurkat cells. J. Biol. Chem. 270:9706–9708.[Abstract/Free Full Text]

Manji, S.S., N.J. Parker, R.T. Williams, S.L. Van, R.B. Pearson, M. Dziadek, and P.J. Smith. 2000. STIM1: a novel phosphoprotein located at the cell surface. Biochim. Biophys. Acta. 1481:147–155.[CrossRef][Medline]

Putney, J.W., Jr. 1997. Capacitative Calcium Entry. Landes Biomedical Publishing, Austin, TX. 210 pp.

Randriamampita, C., and R.Y. Tsien. 1993. Emptying of intracellular Ca²⁺ stores releases a novel small messenger that stimulates Ca²⁺ influx. Nature. 364:809–814.[CrossRef][Medline]

Roos, J., P.J. DiGregorio, A.V. Yeromin, K. Ohlsen, M. Lioudyno, S. Zhang, O. Safrina, J.A. Kozak, S. Wagner, M.D. Cahalan, et al. 2005. STIM1, an essential and conserved component of store-operated calcium channel function. J. Cell Biol. 169:435–445.[Abstract/Free Full Text]

Smani, T., S.I. Zakharov, P. Csutora, E. Leno, E.S. Trepakova, and V.M. Bolotina. 2004. A novel mechanism for the store-operated calcium influx pathway. Nat. Cell Biol. 6:113–120.[CrossRef][Medline]

Williams, R.T., S.S. Manji, N.J. Parker, M.S. Hancock, S.L. Van, J.P. Eid, P.V. Senior, J.S. Kazenwadel, T. Shandala, R. Saint, et al. 2001. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357:673–685.[CrossRef][Medline]

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This Article Abstract Full Text (PDF, 430K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Putney, J. W. Search for Related Content PubMed PubMed Citation Articles by Putney, J. W., Jr. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Related Collections Related Article Social Bookmarking                            What's this?