STIM1 and the noncapacitative ARC channels

Our understanding of the nature and regulation of receptor-activated Ca2+ entry in nonexcitable, cells has recently undergone a radical change that began with the identification of the stromal interacting molecule proteins (e.g., STIM I) as playing a critical role in the regulation of the capacitative, or store-operated, Ca2+ entry. As such, current models emphasize the role of STIM1 located in the endoplasmic reticulum membrane, where it senses the status of the intracellular Ca2+ stores via a luminal N-terminal Ca2+-binding EF-hand domain. Dissociation of Ca2+ from this domain induces the clustering of STIM1 to regions of the ER that lie close to the plasma membrane, where it regulates the activity of the store-operated Ca2+ channels (e.g., CRAC channels). Thus, the specific dependence on store-depletion, and the role of the Ca2+-binding EF-hand domain in this process, are critical to all current models of the action of STIM1 on Ca2+ entry. However, until recently, the effects of STIM1 on other modes of receptor-activated Ca2+ entry have not been examined. Surprisingly, we found that STIM I exerts similar, although not identical, actions on the arachidonic acid-regulated Ca2+-selective (ARC) channels-a widely expressed mode of agonist-activated Ca2+ entry whose activation is completely independent of Ca2+ store depletion. Regulation of the ARC channels by STIM I is not only independent of store depletion, but also of the Ca2+-binding function of the EF-hand, and translocation of STIM1 to the plasma membrane. Instead, it is the pool of STIM1 that constitutively resides in the plasma membrane that is critical for the regulation of the ARC channels. Thus, ARC channel activity is selectively inhibited by exposure of intact cells to an antibody targeting the extracellular N-terminal domain of STIM1. Similarly, introducing mutations in STIM1 that prevent the N-linked glycosylation-dependent constitutive expression of the protein in the plasma membrane specifically inhibits the activity of the ARC channels without affecting the CRAC channels. These studies demonstrate that STIM1 is a far more universal regulator of Ca2+ entry pathways than previously assumed, and has multiple, and entirely distinct, modes of action. Precisely how this same protein can act in such separate and specific ways on these different pathways of agonist-activated Ca2+ entry remains an intriguing, yet currently unresolved, question. (C) 2007 Elsevier Ltd. All rights reserved.