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A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel.
Channels (Austin). 2012 Sep-Oct; 6(5):370-8.C

Abstract

The Orai family of calcium channels includes the store-operated CRAC channels and store-independent, arachidonic acid (AA)-regulated ARC channels. Both depend on STIM1 for their activation but, whereas CRAC channel activation involves sensing the depletion of intracellular calcium stores via a luminal N terminal EF-hand of STIM1 in the endoplasmic reticulum (ER) membrane, ARC channels are exclusively activated by the pool of STIM1 that constitutively resides in the plasma membrane (PM). Here, the EF-hand is extracellular and unlikely to ever lose its bound calcium, suggesting that STIM1-dependent activation of ARC channels is very different from that of CRAC channels. We now show that attachment of the cytosolic portion of STIM1 to the inner face of the PM via an N terminal Lck-domain sequence is sufficient to enable normal AA-dependent activation of ARC channels, while failing to allow activation of store-operated CRAC channels. Introduction of a point mutation within the Lck-domain resulted in the loss of both PM localization and ARC channel activation. Reversing the orientation of the PM-anchored STIM1 C terminus via a C-terminal CAAX-box fails to support either CRAC or ARC channel activation. Finally, the Lck-anchored STIM1 C-terminal domain also enabled the exclusive activation of the ARC channels following physiological agonist addition. These data demonstrate that simple tethering of the cytosolic C-terminal domain of STIM1 to the inner face of the PM is sufficient to allow the full, normal and exclusive activation of ARC channels, and that the N-terminal regions of STIM1 (including the EF-hand domain) play no significant role in this activation.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

22992514

Citation

Thompson, Jill L., and Trevor J. Shuttleworth. "A Plasma Membrane-targeted Cytosolic Domain of STIM1 Selectively Activates ARC Channels, an Arachidonate-regulated Store-independent Orai Channel." Channels (Austin, Tex.), vol. 6, no. 5, 2012, pp. 370-8.
Thompson JL, Shuttleworth TJ. A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel. Channels (Austin). 2012;6(5):370-8.
Thompson, J. L., & Shuttleworth, T. J. (2012). A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel. Channels (Austin, Tex.), 6(5), 370-8. https://doi.org/10.4161/chan.21947
Thompson JL, Shuttleworth TJ. A Plasma Membrane-targeted Cytosolic Domain of STIM1 Selectively Activates ARC Channels, an Arachidonate-regulated Store-independent Orai Channel. Channels (Austin). 2012 Sep-Oct;6(5):370-8. PubMed PMID: 22992514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel. AU - Thompson,Jill L, AU - Shuttleworth,Trevor J, Y1 - 2012/09/01/ PY - 2012/9/21/entrez PY - 2012/9/21/pubmed PY - 2013/5/23/medline SP - 370 EP - 8 JF - Channels (Austin, Tex.) JO - Channels (Austin) VL - 6 IS - 5 N2 - The Orai family of calcium channels includes the store-operated CRAC channels and store-independent, arachidonic acid (AA)-regulated ARC channels. Both depend on STIM1 for their activation but, whereas CRAC channel activation involves sensing the depletion of intracellular calcium stores via a luminal N terminal EF-hand of STIM1 in the endoplasmic reticulum (ER) membrane, ARC channels are exclusively activated by the pool of STIM1 that constitutively resides in the plasma membrane (PM). Here, the EF-hand is extracellular and unlikely to ever lose its bound calcium, suggesting that STIM1-dependent activation of ARC channels is very different from that of CRAC channels. We now show that attachment of the cytosolic portion of STIM1 to the inner face of the PM via an N terminal Lck-domain sequence is sufficient to enable normal AA-dependent activation of ARC channels, while failing to allow activation of store-operated CRAC channels. Introduction of a point mutation within the Lck-domain resulted in the loss of both PM localization and ARC channel activation. Reversing the orientation of the PM-anchored STIM1 C terminus via a C-terminal CAAX-box fails to support either CRAC or ARC channel activation. Finally, the Lck-anchored STIM1 C-terminal domain also enabled the exclusive activation of the ARC channels following physiological agonist addition. These data demonstrate that simple tethering of the cytosolic C-terminal domain of STIM1 to the inner face of the PM is sufficient to allow the full, normal and exclusive activation of ARC channels, and that the N-terminal regions of STIM1 (including the EF-hand domain) play no significant role in this activation. SN - 1933-6969 UR - https://www.unboundmedicine.com/medline/citation/22992514/A_plasma_membrane_targeted_cytosolic_domain_of_STIM1_selectively_activates_ARC_channels_an_arachidonate_regulated_store_independent_Orai_channel_ L2 - https://www.tandfonline.com/doi/full/10.4161/chan.21947 DB - PRIME DP - Unbound Medicine ER -