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2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size.
J Biol Chem. 2008 Jul 18; 283(29):20261-7.JB

Abstract

Stim1 in the endoplasmic reticulum and the three Orai (also termed CRACM) channels in the plasma-membrane are main components of native Ca(2+) release-activated Ca(2+) channels. A pharmacological hallmark of these channels is their distinct sensitivity to 2-aminoethoxydiphenyl borate (2-APB). Here we report that Orai3 currents can be robustly stimulated by 75 microm 2-APB independent of Stim1, whereas 2-APB at similar concentrations inhibited store-operated Orai1 currents. 2-APB did not only promote currents through Orai3 channels but also dramatically altered ion selectivity of Orai3 channels. This allowed for permeation of monovalent cations both in the inward as well as outward direction, which is in sharp contrast to the high Ca(2+) selectivity of store-operated Orai3 currents. An Orai3-R66W mutant, which lacked in analogy to the severe combined immune deficiency mutant Orai1-R91W store-operated activation, was also found to be resistant to 2-APB stimulation. The change in selectivity by 2-APB was associated with an increase in Orai3 minimum pore size from about 3.8A to more than 5.34 A. In line with a potential interaction of 2-APB with the Orai3 pore, among three pore mutants tested, the Orai3 E165Q mutant particularly resembled in its permeation properties those of 2-APB stimulated Orai3 and additionally exhibited a reduced response to 2-APB. In aggregate, stimulation of Orai3 currents by 2-APB occurred along with an alteration of the permeation pathway that represents a unique mechanism for regulating ion channel selectivity by chemical compounds.

Authors+Show Affiliations

Institute of Biophysics, University of Linz, Linz, Austria. rainer.schindl@jku.atNo affiliation info availableNo affiliation info availableNo 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

18499656

Citation

Schindl, Rainer, et al. "2-aminoethoxydiphenyl Borate Alters Selectivity of Orai3 Channels By Increasing Their Pore Size." The Journal of Biological Chemistry, vol. 283, no. 29, 2008, pp. 20261-7.
Schindl R, Bergsmann J, Frischauf I, et al. 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. J Biol Chem. 2008;283(29):20261-7.
Schindl, R., Bergsmann, J., Frischauf, I., Derler, I., Fahrner, M., Muik, M., Fritsch, R., Groschner, K., & Romanin, C. (2008). 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. The Journal of Biological Chemistry, 283(29), 20261-7. https://doi.org/10.1074/jbc.M803101200
Schindl R, et al. 2-aminoethoxydiphenyl Borate Alters Selectivity of Orai3 Channels By Increasing Their Pore Size. J Biol Chem. 2008 Jul 18;283(29):20261-7. PubMed PMID: 18499656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. AU - Schindl,Rainer, AU - Bergsmann,Judith, AU - Frischauf,Irene, AU - Derler,Isabella, AU - Fahrner,Marc, AU - Muik,Martin, AU - Fritsch,Reinhard, AU - Groschner,Klaus, AU - Romanin,Christoph, Y1 - 2008/05/21/ PY - 2008/5/24/pubmed PY - 2008/9/4/medline PY - 2008/5/24/entrez SP - 20261 EP - 7 JF - The Journal of biological chemistry JO - J Biol Chem VL - 283 IS - 29 N2 - Stim1 in the endoplasmic reticulum and the three Orai (also termed CRACM) channels in the plasma-membrane are main components of native Ca(2+) release-activated Ca(2+) channels. A pharmacological hallmark of these channels is their distinct sensitivity to 2-aminoethoxydiphenyl borate (2-APB). Here we report that Orai3 currents can be robustly stimulated by 75 microm 2-APB independent of Stim1, whereas 2-APB at similar concentrations inhibited store-operated Orai1 currents. 2-APB did not only promote currents through Orai3 channels but also dramatically altered ion selectivity of Orai3 channels. This allowed for permeation of monovalent cations both in the inward as well as outward direction, which is in sharp contrast to the high Ca(2+) selectivity of store-operated Orai3 currents. An Orai3-R66W mutant, which lacked in analogy to the severe combined immune deficiency mutant Orai1-R91W store-operated activation, was also found to be resistant to 2-APB stimulation. The change in selectivity by 2-APB was associated with an increase in Orai3 minimum pore size from about 3.8A to more than 5.34 A. In line with a potential interaction of 2-APB with the Orai3 pore, among three pore mutants tested, the Orai3 E165Q mutant particularly resembled in its permeation properties those of 2-APB stimulated Orai3 and additionally exhibited a reduced response to 2-APB. In aggregate, stimulation of Orai3 currents by 2-APB occurred along with an alteration of the permeation pathway that represents a unique mechanism for regulating ion channel selectivity by chemical compounds. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18499656/2_aminoethoxydiphenyl_borate_alters_selectivity_of_Orai3_channels_by_increasing_their_pore_size_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)59681-6 DB - PRIME DP - Unbound Medicine ER -