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The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits.
J Physiol. 2009 Sep 01; 587(Pt 17):4181-97.JP

Abstract

The activation of Ca(2+) entry is a critical component of agonist-induced cytosolic Ca(2+) signals in non-excitable cells. Although a variety of different channels may be involved in such entry, the recent identification of the STIM and Orai proteins has focused attention on the channels in which these proteins play a key role. To date, two distinct highly Ca(2+)-selective STIM1-regulated and Orai-based channels have been identified - the store-operated CRAC channels and the store-independent arachidonic acid activated ARC channels. In contrast to the CRAC channels, where the channel pore is composed of only Orai1 subunits, both Orai1 and Orai3 subunits are essential components of the ARC channel pore. Using an approach involving the co-expression of a dominant-negative Orai1 monomer along with different preassembled concatenated Orai1 constructs, we recently demonstrated that the functional CRAC channel pore is formed by a homotetrameric assembly of Orai1 subunits. Here, we use a similar approach to demonstrate that the functional ARC channel pore is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits. Expression of concatenated pentameric constructs with this stoichiometry results in the appearance of large currents that display all the key biophysical and pharmacological features of the endogenous ARC channels. They also replicate the essential regulatory characteristics of native ARC channels including specific activation by low concentrations of arachidonic acid, complete independence of store depletion, and an absolute requirement for the pool of STIM1 that constitutively resides in the plasma membrane.

Authors+Show Affiliations

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA. trevor_shuttleworth@urmc.rochester.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19622606

Citation

Mignen, Olivier, et al. "The Molecular Architecture of the Arachidonate-regulated Ca2+-selective ARC Channel Is a Pentameric Assembly of Orai1 and Orai3 Subunits." The Journal of Physiology, vol. 587, no. Pt 17, 2009, pp. 4181-97.
Mignen O, Thompson JL, Shuttleworth TJ. The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. J Physiol (Lond). 2009;587(Pt 17):4181-97.
Mignen, O., Thompson, J. L., & Shuttleworth, T. J. (2009). The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. The Journal of Physiology, 587(Pt 17), 4181-97. https://doi.org/10.1113/jphysiol.2009.174193
Mignen O, Thompson JL, Shuttleworth TJ. The Molecular Architecture of the Arachidonate-regulated Ca2+-selective ARC Channel Is a Pentameric Assembly of Orai1 and Orai3 Subunits. J Physiol (Lond). 2009 Sep 1;587(Pt 17):4181-97. PubMed PMID: 19622606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. AU - Mignen,Olivier, AU - Thompson,Jill L, AU - Shuttleworth,Trevor J, Y1 - 2009/07/21/ PY - 2009/7/23/entrez PY - 2009/7/23/pubmed PY - 2009/12/16/medline SP - 4181 EP - 97 JF - The Journal of physiology JO - J. Physiol. (Lond.) VL - 587 IS - Pt 17 N2 - The activation of Ca(2+) entry is a critical component of agonist-induced cytosolic Ca(2+) signals in non-excitable cells. Although a variety of different channels may be involved in such entry, the recent identification of the STIM and Orai proteins has focused attention on the channels in which these proteins play a key role. To date, two distinct highly Ca(2+)-selective STIM1-regulated and Orai-based channels have been identified - the store-operated CRAC channels and the store-independent arachidonic acid activated ARC channels. In contrast to the CRAC channels, where the channel pore is composed of only Orai1 subunits, both Orai1 and Orai3 subunits are essential components of the ARC channel pore. Using an approach involving the co-expression of a dominant-negative Orai1 monomer along with different preassembled concatenated Orai1 constructs, we recently demonstrated that the functional CRAC channel pore is formed by a homotetrameric assembly of Orai1 subunits. Here, we use a similar approach to demonstrate that the functional ARC channel pore is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits. Expression of concatenated pentameric constructs with this stoichiometry results in the appearance of large currents that display all the key biophysical and pharmacological features of the endogenous ARC channels. They also replicate the essential regulatory characteristics of native ARC channels including specific activation by low concentrations of arachidonic acid, complete independence of store depletion, and an absolute requirement for the pool of STIM1 that constitutively resides in the plasma membrane. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/19622606/The_molecular_architecture_of_the_arachidonate_regulated_Ca2+_selective_ARC_channel_is_a_pentameric_assembly_of_Orai1_and_Orai3_subunits_ L2 - https://doi.org/10.1113/jphysiol.2009.174193 DB - PRIME DP - Unbound Medicine ER -