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- W1978576786 abstract "The Orai family of Ca2+ channels includes the store-operated CRAC channels and store-independent, arachidonic acid (AA)-activated ARC channels. Although both channels are dependent on STIM1 for their activation, they differ in the pool of STIM1 responsible. Physiologically, CRAC channel activation relies on a loss of Ca2+ from a luminal N-terminal EF-hand domain of STIM1 resident in the ER membrane. However, ARC channels are exclusively regulated by the pool of STIM1 that is constitutively located in the plasma membrane (PM). Here, the EF-hand is extracellular and is unlikely to ever lose its bound Ca2+ - suggesting that STIM1-dependent activation of the ARC channels is very different from that of the CRAC channels. Expression of just the cytosolic C-terminal region of STIM1 in HEK293 cells resulted in the complete loss of significant CRAC or ARC channel currents following store-depletion or AA addition, respectively. However, attachment of the same STIM1 C-terminus to the inner face of the PM via an N-terminal sequence based on the SH4 domain of Lck, resulted in the full restoration of normal AA-activated ARC channel currents. Store-operated CRAC channel currents, however, were not restored - an effect confirmed in RBL cells, whose endogenous CRAC currents are ∼4-5 times larger than those in HEK293 cells. Finally, introduction of a point mutation within the Lck sequence that blocks myristoylation/palmitoylation of this domain, with the consequent loss of PM localization, resulted in the failure of effective ARC channel activation. These data indicate that N-terminal regions of STIM1 (including the EF-hand and SAM domains) play no significant role in AA-dependent activation of the ARC channels, and that the simple location of the C-terminal domain to the cytosolic face of the PM is all that is required." @default.
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- W1978576786 date "2012-01-01" @default.
- W1978576786 modified "2023-09-26" @default.
- W1978576786 title "Activation of ARC Channels, a Noncapacitative Orai Channel, is Independent of the N-Terminal Domains of STIM1" @default.
- W1978576786 doi "https://doi.org/10.1016/j.bpj.2011.11.2324" @default.
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