Ca2+ Selectivity and Fatty Acid Specificity of the Noncapacitative, Arachidonate-regulated Ca2+ (ARC) Channels

Mignen, Olivier; Thompson, J.; Shuttleworth, Trevor J.

doi:10.1074/jbc.m212536200

Cited by 100 publications

(113 citation statements)

References 57 publications

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“…Among the second messengers proposed to play a role in NSOCE activation, arachidonic acid (AA) itself and some of its metabolites induce calcium increases directly correlated with cell proliferation in different cell types, including endothelial cells (11)(12)(13). Although several reports have implicated AA metabolites in the control of the angiogenic process with a key role in cell proliferation, cell motility, and angiogenic process (14)(15)(16), little is known about the direct role of AA.…”

Section: Introductionmentioning

confidence: 99%

Arachidonic Acid–Induced Ca2+ Entry Is Involved in Early Steps of Tumor Angiogenesis

Fiorio

Grange

Antoniotti

et al. 2008

Molecular Cancer Research

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Growth factor -induced intracellular calcium signals in endothelial cells regulate cytosolic and nuclear events involved in the angiogenic process. Among the intracellular messengers released after proangiogenic stimulation, arachidonic acid (AA) plays a key role and its effects are strictly related to calcium homeostasis and cell proliferation. Here, we studied AA-induced intracellular calcium signals in endothelial cells derived from human breast carcinomas (B-TEC). AA promotes B-TEC proliferation and organization of vessel-like structures in vitro. The effect is directly mediated by the fatty acid without a significant contribution of its metabolites. AA induces Ca 2+ i signals in the entire capillary-like structure during the early phases of tubulogenesis in vitro. No such responses are detectable in B-TECs organized in more structured tubules. In B-TECs growing in monolayer, AA induces two different signals: a Ca 2+ i increase due to Ca 2+ entry and an inhibition of store-dependent Ca 2+ entry induced by thapsigargin or ATP. An inhibitor of Ca 2+ entry and angiogenesis, carboxyamidotriazole, significantly and specifically decreases AA-induced B-TEC tubulogenesis, as well as AA-induced Ca 2+ signals in B-TECs. We conclude that (a) AA-activated Ca 2+ entry is associated with the progression through the early phases of angiogenesis, mainly involving proliferation and tubulogenesis, and it is down-regulated during the reorganization of tumor-derived endothelial cells in capillary-like structures; and (b) inhibition of AA-induced Ca 2+ entry may contribute to the antiangiogenic action of carboxyamidotriazole. (Mol Cancer Res 2008;6(4):535 -45)

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Section: Introductionmentioning

confidence: 99%

Arachidonic Acid–Induced Ca2+ Entry Is Involved in Early Steps of Tumor Angiogenesis

Fiorio

Grange

Antoniotti

et al. 2008

Molecular Cancer Research

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“…2C). In addition to store-operated Ca 2ϩ entry, some cell types express arachidonate-regulated Ca 2ϩ -selective (ARC) channels, which are gated by arachidonic acid through a mechanism that does not involve store emptying (29,30). Two arguments suggest that under our experimental conditions, ARC channels make little contribution to the overall Ca 2ϩ signal.…”

Section: The Crac Channel Inhibitors 2-aminoethoxydiphenylborate (2-amentioning

confidence: 85%

“…Although we found that arachidonic acid can partially inhibit both I CRAC and thapsigargin-evoked Ca 2ϩ influx in Fura 2-loaded cells by up to 70% (data not shown), this occurs only at relatively high concentra- tions (10 -50 M). As pointed out by Shuttleworth and colleagues (29), these levels exceed the critical micelle concentration and could reflect nonspecific effects on the physical properties or structural integrity of the plasma membrane. At physiologically relevant concentrations (1-5 M; see Ref.…”

Section: Camentioning

confidence: 99%

“…First, after a Ca 2ϩ plateau had been reached following readmission of external Ca 2ϩ to thapsigargin-treated cells, application of 20 M 2-APB inhibited the Ca 2ϩ signal by 81 Ϯ 11%. Although 2-APB inhibits CRAC channels, it has no effect on ARC channels (29). Second, even modest Ca 2ϩ entry through the storeoperated pathway rapidly inhibits ARC channels through a mechanism involving calcineurin (30).…”

Section: The Crac Channel Inhibitors 2-aminoethoxydiphenylborate (2-amentioning

confidence: 99%

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Close Functional Coupling between Ca2+ Release-activated Ca2+ Channels, Arachidonic Acid Release, and Leukotriene C4 Secretion

Chang

Parekh

2004

Journal of Biological Chemistry

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In non-excitable cells, one major route for Ca 2؉ influx is through store-operated Ca 2؉ channels in the plasma membrane. These channels are activated by the emptying of intracellular Ca 2؉ stores, and in some cell types, particularly of hemopoietic origin, store-operated influx occurs through Ca 2؉ release-activated Ca 2؉ (CRAC) channels. However, little is known about the downstream consequences of CRAC channel activation. Here, we report that Ca 2؉ entry through CRAC channels stimulates arachidonic acid production, whereas Ca 2؉ release from the stores is ineffective even though the latter evokes a robust intracellular Ca 2؉ signal. We find that arachidonic acid released by Ca 2؉ entering through CRAC channels is used to synthesize the potent paracrine proinflammatory signal leukotriene C 4 (LTC 4 ). Both pharmacological inhibitors of CRAC channels and mitochondrial depolarization, which impairs CRAC channel activity, suppress arachidonic acid release and LTC 4 secretion. Thus, arachidonic acid release is preferentially stimulated by elevated subplasmalemmal Ca 2؉ levels due to open CRAC channels, suggesting that the enzyme is located close to the CRAC channels. Our results also identify a novel role for CRAC channels, namely the activation of a downstream signal transduction pathway resulting in the secretion of LTC 4 . Finally, mitochondria are key determinants of the generation of both intracellular (arachidonic acid) and paracrine (LTC 4 ) signals through their effects on CRAC channel activity.

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“…Unlike CRAC channels and the endogenous SOC channels, ARC channels do not show any fast inactivation and they are not inhibited by reductions in extracellular pH. Their sensitivity to the widely used blocker Gd 3+ is similar to that seen with various SOC channels, but they are insensitive to 2-APB (14). Like CRAC channels and voltage- gated Ca 2+ channels, complete removal of external divalent cations permits the permeation of monovalent cations through ARC channels.…”

Section: Properties Of Arc Channelsmentioning

confidence: 87%

ARC Channels: A Novel Pathway for Receptor-Activated Calcium Entry

2004

Self Cite

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2+ions ([Ca 2+ ] i ) is a major component of cellular signals generated by the actions of a variety of hormones and neurotransmitters acting on receptors coupled to phospholipase C (PLC). Such [Ca 2+ ] i signals invariably involve both an inositol 1,4,5-trisphosphate (IP 3 )-mediated release of Ca 2+ from intracellular stores and the activation of an enhanced entry of extracellular Ca 2+ . Although the latter is often critical in achieving an effective sustained response from the cells, our understanding of the nature of the relevant Ca 2+ -entry pathway and its regulation has lagged far behind the study of IP 3 -mediated Ca 2+ release, a fact due, as much as anything, to the technical difficulties involved in directly measuring the activities of the generally small conductances involved.For much of the past 18 years, attention has focused on the so-called "capacitative" or storeoperated mechanism of Ca 2+ entry first defined by Putney (24,25). In this, the two processes that make up PLC-dependent [Ca 2+ ] i signaling are intimately and sequentially linked in that the emptying of agonist-sensitive stores alone is both necessary and sufficient to activate Ca 2+ entry. The channels responsible for this entry are generically described as store-operated channels, the archetypal version of which are the Ca 2+ release-activated Ca 2+ channels (CRAC channels) first described in mast cells and Jurkat cells (8,36). Despite extensive study, the molecular identity of these channels and the precise mechanism whereby depletion of the agonist-sensitive Ca 2+ stores induces their activation have yet to be resolved (20,23). Nevertheless, the role of the CRAC channels and other similar store-operated Ca 2+ -selective channels (SOC channels) in cellular Ca 2+ signaling is clear. Entry through these channels determines the level of the sustained elevation in [Ca 2+ ] i observed following stimulation with high agonist concentrations and is responsible for the subsequent refilling of intracellular agonist-sensitive Ca 2+ stores following termination of the signal. However, it is significant that activation of these channels has been shown to require a rather profound and sustained depletion of the intracellular stores (5, 19), although this issue remains controversial (7). In certain cell types (e.g., T lymphocytes), the limited size of the agonist-sensitive store means that such a profound depletion is readily achieved at all levels of stimulation, and in these cells it seems that CRAC channels provide the principal source of Ca 2+ entry under all conditions (23). In many other cells, however, the oscillatory [Ca 2+ ] i signals typically seen following stimulation at lower, more physiologically relevant agonist concentrations reflect only a transient and/or partial release of Ca 2+ from the stores (21). As discussed above, the precise relationship between the extent of store depletion and the magnitude of the CRAC current that results remains controversial. In contrast, it is clear that the activation of CRAC channels is slow,...

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Ca2+ Selectivity and Fatty Acid Specificity of the Noncapacitative, Arachidonate-regulated Ca2+ (ARC) Channels

Cited by 100 publications

References 57 publications

Arachidonic Acid–Induced Ca2+ Entry Is Involved in Early Steps of Tumor Angiogenesis

Arachidonic Acid–Induced Ca2+ Entry Is Involved in Early Steps of Tumor Angiogenesis

Close Functional Coupling between Ca2+ Release-activated Ca2+ Channels, Arachidonic Acid Release, and Leukotriene C4 Secretion

ARC Channels: A Novel Pathway for Receptor-Activated Calcium Entry

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