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Competitive modulation of Ca2+ release-activated Ca2+ channel gating by STIM1 and 2-aminoethyldiphenyl borate.
J Biol Chem. 2011 Mar 18; 286(11):9429-42.JB

Abstract

Activation of Ca(2+) release-activated Ca(2+) channels by depletion of intracellular Ca(2+) stores involves physical interactions between the endoplasmic reticulum Ca(2+) sensor, STIM1, and the channels composed of Orai subunits. Recent studies indicate that the Orai3 subtype, in addition to being store-operated, is also activated in a store-independent manner by 2-aminoethyldiphenyl borate (2-APB), a small molecule with complex pharmacology. However, it is unknown whether the store-dependent and -independent activation modes of Orai3 channels operate independently or whether there is cross-talk between these activation states. Here we report that in addition to causing direct activation, 2-APB also regulates store-operated gating of Orai3 channels, causing potentiation at low doses and inhibition at high doses. Inhibition of store-operated gating by 2-APB was accompanied by the suppression of several modes of Orai3 channel regulation that depend on STIM1, suggesting that high doses of 2-APB interrupt STIM1-Orai3 coupling. Conversely, STIM1-bound Orai3 (and Orai1) channels resisted direct gating by high doses of 2-APB. The rate of direct 2-APB activation of Orai3 channels increased linearly with the degree of STIM1-Orai3 uncoupling, suggesting that 2-APB has to first disengage STIM1 before it can directly gate Orai3 channels. Collectively, our results indicate that the store-dependent and -independent modes of Ca(2+) release-activated Ca(2+) channel activation are mutually exclusive: channels bound to STIM1 resist 2-APB gating, whereas 2-APB antagonizes STIM1 gating.

Authors+Show Affiliations

Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21193399

Citation

Yamashita, Megumi, et al. "Competitive Modulation of Ca2+ Release-activated Ca2+ Channel Gating By STIM1 and 2-aminoethyldiphenyl Borate." The Journal of Biological Chemistry, vol. 286, no. 11, 2011, pp. 9429-42.
Yamashita M, Somasundaram A, Prakriya M. Competitive modulation of Ca2+ release-activated Ca2+ channel gating by STIM1 and 2-aminoethyldiphenyl borate. J Biol Chem. 2011;286(11):9429-42.
Yamashita, M., Somasundaram, A., & Prakriya, M. (2011). Competitive modulation of Ca2+ release-activated Ca2+ channel gating by STIM1 and 2-aminoethyldiphenyl borate. The Journal of Biological Chemistry, 286(11), 9429-42. https://doi.org/10.1074/jbc.M110.189035
Yamashita M, Somasundaram A, Prakriya M. Competitive Modulation of Ca2+ Release-activated Ca2+ Channel Gating By STIM1 and 2-aminoethyldiphenyl Borate. J Biol Chem. 2011 Mar 18;286(11):9429-42. PubMed PMID: 21193399.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Competitive modulation of Ca2+ release-activated Ca2+ channel gating by STIM1 and 2-aminoethyldiphenyl borate. AU - Yamashita,Megumi, AU - Somasundaram,Agila, AU - Prakriya,Murali, Y1 - 2010/12/30/ PY - 2011/1/4/entrez PY - 2011/1/5/pubmed PY - 2011/5/17/medline SP - 9429 EP - 42 JF - The Journal of biological chemistry JO - J Biol Chem VL - 286 IS - 11 N2 - Activation of Ca(2+) release-activated Ca(2+) channels by depletion of intracellular Ca(2+) stores involves physical interactions between the endoplasmic reticulum Ca(2+) sensor, STIM1, and the channels composed of Orai subunits. Recent studies indicate that the Orai3 subtype, in addition to being store-operated, is also activated in a store-independent manner by 2-aminoethyldiphenyl borate (2-APB), a small molecule with complex pharmacology. However, it is unknown whether the store-dependent and -independent activation modes of Orai3 channels operate independently or whether there is cross-talk between these activation states. Here we report that in addition to causing direct activation, 2-APB also regulates store-operated gating of Orai3 channels, causing potentiation at low doses and inhibition at high doses. Inhibition of store-operated gating by 2-APB was accompanied by the suppression of several modes of Orai3 channel regulation that depend on STIM1, suggesting that high doses of 2-APB interrupt STIM1-Orai3 coupling. Conversely, STIM1-bound Orai3 (and Orai1) channels resisted direct gating by high doses of 2-APB. The rate of direct 2-APB activation of Orai3 channels increased linearly with the degree of STIM1-Orai3 uncoupling, suggesting that 2-APB has to first disengage STIM1 before it can directly gate Orai3 channels. Collectively, our results indicate that the store-dependent and -independent modes of Ca(2+) release-activated Ca(2+) channel activation are mutually exclusive: channels bound to STIM1 resist 2-APB gating, whereas 2-APB antagonizes STIM1 gating. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/21193399/Competitive_modulation_of_Ca2+_release_activated_Ca2+_channel_gating_by_STIM1_and_2_aminoethyldiphenyl_borate_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)51831-0 DB - PRIME DP - Unbound Medicine ER -