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Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1.
J Physiol. 2013 Jul 15; 591(14):3507-23.JP

Abstract

Currently, Orai proteins are known to encode two distinct agonist-activated, highly calcium-selective channels: the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, and the store-independent, arachidonic acid-activated ARC channels. Surprisingly, whilst the trigger for activation of these channels is entirely different, both depend on stromal interacting molecule 1 (STIM1). However, whilst STIM1 in the endoplasmic reticulum membrane is the critical sensor for the depletion of this calcium store that triggers CRAC channel activation, it is the pool of STIM1 constitutively resident in the plasma membrane that is essential for activation of the ARC channels. Here, using a variety of approaches, we show that the key domains within the cytosolic part of STIM1 identified as critical for the activation of CRAC channels are also key for activation of the ARC channels. However, examination of the actual steps involved in such activation reveal marked differences between these two Orai channel types. Specifically, loss of calcium from the EF-hand of STIM1 that forms the key initiation point for activation of the CRAC channels has no effect on ARC channel activity. Secondly, in marked contrast to the dynamic and labile nature of interactions between STIM1 and the CRAC channels, STIM1 in the plasma membrane appears to be constitutively associated with the ARC channels. Finally, specific mutations in STIM1 that induce an extended, constitutively active, conformation for the CRAC channels actually prevent activation of the ARC channels by arachidonic acid. Based on these findings, we propose that the likely role of arachidonic acid lies in inducing the actual gating of the channel.

Authors+Show Affiliations

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23690558

Citation

Thompson, Jill L., and Trevor J. Shuttleworth. "Molecular Basis of Activation of the Arachidonate-regulated Ca2+ (ARC) Channel, a Store-independent Orai Channel, By Plasma Membrane STIM1." The Journal of Physiology, vol. 591, no. 14, 2013, pp. 3507-23.
Thompson JL, Shuttleworth TJ. Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. J Physiol. 2013;591(14):3507-23.
Thompson, J. L., & Shuttleworth, T. J. (2013). Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. The Journal of Physiology, 591(14), 3507-23. https://doi.org/10.1113/jphysiol.2013.256784
Thompson JL, Shuttleworth TJ. Molecular Basis of Activation of the Arachidonate-regulated Ca2+ (ARC) Channel, a Store-independent Orai Channel, By Plasma Membrane STIM1. J Physiol. 2013 Jul 15;591(14):3507-23. PubMed PMID: 23690558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. AU - Thompson,Jill L, AU - Shuttleworth,Trevor J, Y1 - 2013/05/20/ PY - 2013/5/22/entrez PY - 2013/5/22/pubmed PY - 2014/2/5/medline SP - 3507 EP - 23 JF - The Journal of physiology JO - J Physiol VL - 591 IS - 14 N2 - Currently, Orai proteins are known to encode two distinct agonist-activated, highly calcium-selective channels: the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, and the store-independent, arachidonic acid-activated ARC channels. Surprisingly, whilst the trigger for activation of these channels is entirely different, both depend on stromal interacting molecule 1 (STIM1). However, whilst STIM1 in the endoplasmic reticulum membrane is the critical sensor for the depletion of this calcium store that triggers CRAC channel activation, it is the pool of STIM1 constitutively resident in the plasma membrane that is essential for activation of the ARC channels. Here, using a variety of approaches, we show that the key domains within the cytosolic part of STIM1 identified as critical for the activation of CRAC channels are also key for activation of the ARC channels. However, examination of the actual steps involved in such activation reveal marked differences between these two Orai channel types. Specifically, loss of calcium from the EF-hand of STIM1 that forms the key initiation point for activation of the CRAC channels has no effect on ARC channel activity. Secondly, in marked contrast to the dynamic and labile nature of interactions between STIM1 and the CRAC channels, STIM1 in the plasma membrane appears to be constitutively associated with the ARC channels. Finally, specific mutations in STIM1 that induce an extended, constitutively active, conformation for the CRAC channels actually prevent activation of the ARC channels by arachidonic acid. Based on these findings, we propose that the likely role of arachidonic acid lies in inducing the actual gating of the channel. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/23690558/Molecular_basis_of_activation_of_the_arachidonate_regulated_Ca2+__ARC__channel_a_store_independent_Orai_channel_by_plasma_membrane_STIM1_ L2 - https://doi.org/10.1113/jphysiol.2013.256784 DB - PRIME DP - Unbound Medicine ER -