STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation

Suhel Parvez, Andreas Beck, Christine Peinelt, Jonathan Soboloff, Annette Lis, Mahealani Monteilh-Zoller, Donald L. Gill, Andrea Fleig, Reinhold Penner

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

STIM1 and CRACM1 (or Orai1) are essential molecular components mediating store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) currents. Although STIM1 acts as a luminal Ca2+ sensor in the endoplasmic reticulum (ER), the function of STIM2 remains unclear. Here we reveal that STIM2 has two distinct modes of activating CRAC channels: a store-operated mode that is activated through depletion of ER Ca2+ stores by inositol 1,4,5-trisphosphate (InsP3) and store-independent activation that is mediated by cell dialysis during whole-cell perfusion. Both modes are regulated by calmodulin (CaM). The store-operated mode is transient in intact cells, possibly reflecting recruitment of CaM, whereas loss of CaM in perfused cells accounts for the persistence of the store-independent mode. The inhibition by CaM can be reversed by 2-aminoethoxydiphenyl borate (2-APB), resulting in rapid, store-independent activation of CRAC channels. The aminoglycoside antibiotic G418 is a highly specific and potent inhibitor of STIM2-dependent CRAC channel activation. The results reveal a novel bimodal control of CRAC channels by STIM2, the store dependence and CaM regulation, which indicates that the STIM2/CRACM1 complex may be under the control of both luminal and cytoplasmic Ca2+ levels.

Original languageEnglish (US)
Pages (from-to)752-761
Number of pages10
JournalFASEB Journal
Volume22
Issue number3
DOIs
StatePublished - Mar 1 2008

Fingerprint

Calmodulin
Chemical activation
calcium
Proteins
proteins
calmodulin
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate
Dialysis
Aminoglycosides
Perfusion
Stromal Interaction Molecule 2
Anti-Bacterial Agents
endoplasmic reticulum
Sensors
geneticin
aminoglycoside antibiotics
cells
borates
dialysis

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Parvez, S., Beck, A., Peinelt, C., Soboloff, J., Lis, A., Monteilh-Zoller, M., ... Penner, R. (2008). STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB Journal, 22(3), 752-761. https://doi.org/10.1096/fj.07-9449com
Parvez, Suhel ; Beck, Andreas ; Peinelt, Christine ; Soboloff, Jonathan ; Lis, Annette ; Monteilh-Zoller, Mahealani ; Gill, Donald L. ; Fleig, Andrea ; Penner, Reinhold. / STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. In: FASEB Journal. 2008 ; Vol. 22, No. 3. pp. 752-761.
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Parvez, S, Beck, A, Peinelt, C, Soboloff, J, Lis, A, Monteilh-Zoller, M, Gill, DL, Fleig, A & Penner, R 2008, 'STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation', FASEB Journal, vol. 22, no. 3, pp. 752-761. https://doi.org/10.1096/fj.07-9449com

STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. / Parvez, Suhel; Beck, Andreas; Peinelt, Christine; Soboloff, Jonathan; Lis, Annette; Monteilh-Zoller, Mahealani; Gill, Donald L.; Fleig, Andrea; Penner, Reinhold.

In: FASEB Journal, Vol. 22, No. 3, 01.03.2008, p. 752-761.

Research output: Contribution to journalArticle

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T1 - STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation

AU - Parvez, Suhel

AU - Beck, Andreas

AU - Peinelt, Christine

AU - Soboloff, Jonathan

AU - Lis, Annette

AU - Monteilh-Zoller, Mahealani

AU - Gill, Donald L.

AU - Fleig, Andrea

AU - Penner, Reinhold

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N2 - STIM1 and CRACM1 (or Orai1) are essential molecular components mediating store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) currents. Although STIM1 acts as a luminal Ca2+ sensor in the endoplasmic reticulum (ER), the function of STIM2 remains unclear. Here we reveal that STIM2 has two distinct modes of activating CRAC channels: a store-operated mode that is activated through depletion of ER Ca2+ stores by inositol 1,4,5-trisphosphate (InsP3) and store-independent activation that is mediated by cell dialysis during whole-cell perfusion. Both modes are regulated by calmodulin (CaM). The store-operated mode is transient in intact cells, possibly reflecting recruitment of CaM, whereas loss of CaM in perfused cells accounts for the persistence of the store-independent mode. The inhibition by CaM can be reversed by 2-aminoethoxydiphenyl borate (2-APB), resulting in rapid, store-independent activation of CRAC channels. The aminoglycoside antibiotic G418 is a highly specific and potent inhibitor of STIM2-dependent CRAC channel activation. The results reveal a novel bimodal control of CRAC channels by STIM2, the store dependence and CaM regulation, which indicates that the STIM2/CRACM1 complex may be under the control of both luminal and cytoplasmic Ca2+ levels.

AB - STIM1 and CRACM1 (or Orai1) are essential molecular components mediating store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) currents. Although STIM1 acts as a luminal Ca2+ sensor in the endoplasmic reticulum (ER), the function of STIM2 remains unclear. Here we reveal that STIM2 has two distinct modes of activating CRAC channels: a store-operated mode that is activated through depletion of ER Ca2+ stores by inositol 1,4,5-trisphosphate (InsP3) and store-independent activation that is mediated by cell dialysis during whole-cell perfusion. Both modes are regulated by calmodulin (CaM). The store-operated mode is transient in intact cells, possibly reflecting recruitment of CaM, whereas loss of CaM in perfused cells accounts for the persistence of the store-independent mode. The inhibition by CaM can be reversed by 2-aminoethoxydiphenyl borate (2-APB), resulting in rapid, store-independent activation of CRAC channels. The aminoglycoside antibiotic G418 is a highly specific and potent inhibitor of STIM2-dependent CRAC channel activation. The results reveal a novel bimodal control of CRAC channels by STIM2, the store dependence and CaM regulation, which indicates that the STIM2/CRACM1 complex may be under the control of both luminal and cytoplasmic Ca2+ levels.

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Parvez S, Beck A, Peinelt C, Soboloff J, Lis A, Monteilh-Zoller M et al. STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB Journal. 2008 Mar 1;22(3):752-761. https://doi.org/10.1096/fj.07-9449com