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A Ca2(+)release-activated Ca2(+) (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2(+)-dependent inactivation of ORAI1 channels.
J Biol Chem. 2009 Sep 11; 284(37):24933-8.JB

Abstract

STIM1 and ORAI1, the two limiting components in the Ca(2+) release-activated Ca(2+) (CRAC) signaling cascade, have been reported to interact upon store depletion, culminating in CRAC current activation. We have recently identified a modulatory domain between amino acids 474 and 485 in the cytosolic part of STIM1 that comprises 7 negatively charged residues. A STIM1 C-terminal fragment lacking this domain exhibits enhanced interaction with ORAI1 and 2-3-fold higher ORAI1/CRAC current densities. Here we focused on the role of this CRAC modulatory domain (CMD) in the fast inactivation of ORAI1/CRAC channels, utilizing the whole-cell patch clamp technique. STIM1 mutants either with C-terminal deletions including CMD or with 7 alanines replacing the negative amino acids within CMD gave rise to ORAI1 currents that displayed significantly reduced or even abolished inactivation when compared with STIM1 mutants with preserved CMD. Consistent results were obtained with cytosolic C-terminal fragments of STIM1, both in ORAI1-expressing HEK 293 cells and in RBL-2H3 mast cells containing endogenous CRAC channels. Inactivation of the latter, however, was much more pronounced than that of ORAI1. The extent of inactivation of ORAI3 channels, which is also considerably more prominent than that of ORAI1, was also substantially reduced by co-expression of STIM1 constructs missing CMD. Regarding the dependence of inactivation on Ca(2+), a decrease in intracellular Ca(2+) chelator concentrations promoted ORAI1 current fast inactivation, whereas Ba(2+) substitution for extracellular Ca(2+) completely abrogated it. In summary, CMD within the STIM1 cytosolic part provides a negative feedback signal to Ca(2+) entry by triggering fast Ca(2+)-dependent inactivation of ORAI/CRAC channels.

Authors+Show Affiliations

Institute of Biophysics, University of Linz, A-4040 Linz, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19622747

Citation

Derler, Isabella, et al. "A Ca2(+)release-activated Ca2(+) (CRAC) Modulatory Domain (CMD) Within STIM1 Mediates Fast Ca2(+)-dependent Inactivation of ORAI1 Channels." The Journal of Biological Chemistry, vol. 284, no. 37, 2009, pp. 24933-8.
Derler I, Fahrner M, Muik M, et al. A Ca2(+)release-activated Ca2(+) (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2(+)-dependent inactivation of ORAI1 channels. J Biol Chem. 2009;284(37):24933-8.
Derler, I., Fahrner, M., Muik, M., Lackner, B., Schindl, R., Groschner, K., & Romanin, C. (2009). A Ca2(+)release-activated Ca2(+) (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2(+)-dependent inactivation of ORAI1 channels. The Journal of Biological Chemistry, 284(37), 24933-8. https://doi.org/10.1074/jbc.C109.024083
Derler I, et al. A Ca2(+)release-activated Ca2(+) (CRAC) Modulatory Domain (CMD) Within STIM1 Mediates Fast Ca2(+)-dependent Inactivation of ORAI1 Channels. J Biol Chem. 2009 Sep 11;284(37):24933-8. PubMed PMID: 19622747.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Ca2(+)release-activated Ca2(+) (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2(+)-dependent inactivation of ORAI1 channels. AU - Derler,Isabella, AU - Fahrner,Marc, AU - Muik,Martin, AU - Lackner,Barbara, AU - Schindl,Rainer, AU - Groschner,Klaus, AU - Romanin,Christoph, Y1 - 2009/07/21/ PY - 2009/7/23/entrez PY - 2009/7/23/pubmed PY - 2009/11/3/medline SP - 24933 EP - 8 JF - The Journal of biological chemistry JO - J Biol Chem VL - 284 IS - 37 N2 - STIM1 and ORAI1, the two limiting components in the Ca(2+) release-activated Ca(2+) (CRAC) signaling cascade, have been reported to interact upon store depletion, culminating in CRAC current activation. We have recently identified a modulatory domain between amino acids 474 and 485 in the cytosolic part of STIM1 that comprises 7 negatively charged residues. A STIM1 C-terminal fragment lacking this domain exhibits enhanced interaction with ORAI1 and 2-3-fold higher ORAI1/CRAC current densities. Here we focused on the role of this CRAC modulatory domain (CMD) in the fast inactivation of ORAI1/CRAC channels, utilizing the whole-cell patch clamp technique. STIM1 mutants either with C-terminal deletions including CMD or with 7 alanines replacing the negative amino acids within CMD gave rise to ORAI1 currents that displayed significantly reduced or even abolished inactivation when compared with STIM1 mutants with preserved CMD. Consistent results were obtained with cytosolic C-terminal fragments of STIM1, both in ORAI1-expressing HEK 293 cells and in RBL-2H3 mast cells containing endogenous CRAC channels. Inactivation of the latter, however, was much more pronounced than that of ORAI1. The extent of inactivation of ORAI3 channels, which is also considerably more prominent than that of ORAI1, was also substantially reduced by co-expression of STIM1 constructs missing CMD. Regarding the dependence of inactivation on Ca(2+), a decrease in intracellular Ca(2+) chelator concentrations promoted ORAI1 current fast inactivation, whereas Ba(2+) substitution for extracellular Ca(2+) completely abrogated it. In summary, CMD within the STIM1 cytosolic part provides a negative feedback signal to Ca(2+) entry by triggering fast Ca(2+)-dependent inactivation of ORAI/CRAC channels. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/19622747/A_Ca2_+_release_activated_Ca2_+___CRAC__modulatory_domain__CMD__within_STIM1_mediates_fast_Ca2_+__dependent_inactivation_of_ORAI1_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)30581-0 DB - PRIME DP - Unbound Medicine ER -