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Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia.

ABSTRACT: Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store-operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown.The goal of this study was to determine the agonist-evoked Ca(2+) entry pathway contributed by Orai3; Orai3 potential upregulation and role during neointima formation after balloon injury of rat carotid arteries.Ca(2+) imaging and patch-clamp recordings showed that although the platelet-derived growth factor activates the canonical Ca(2+) release-activated Ca(2+) channels via store depletion in VSMC, the pathophysiological agonist thrombin activates a distinct Ca(2+)-selective channel contributed by Orai1, Orai3, and stromal interacting molecule1 in the same cells. Unexpectedly, Ca(2+) store depletion is not required for activation of Orai1/3 channel by thrombin. Rather, the signal for Orai1/3 channel activation is cytosolic leukotrieneC4 produced downstream thrombin receptor stimulation through the catalytic activity of leukotrieneC4 synthase. Importantly, Orai3 is upregulated in an animal model of VSMC neointimal remodeling, and in vivo Orai3 knockdown inhibits neointima formation.These results demonstrate that distinct native Ca(2+)-selective Orai channels are activated by different agonists/pathways and uncover a mechanism whereby leukotrieneC4 acts through hitherto unknown intracrine mode to elicit store-independent Ca(2+) signaling that promotes vascular occlusive disease. Orai3 and Orai3-containing channels provide novel targets for control of VSMC remodeling during vascular injury or disease.

SUBMITTER: Gonzalez-Cobos JC

PROVIDER: S-EPMC3658112 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia.

González-Cobos José C JC Zhang Xuexin X Zhang Wei W Ruhle Brian B Motiani Rajender K RK Schindl Rainer R Muik Martin M Spinelli Amy M AM Bisaillon Jonathan M JM Shinde Arti V AV Fahrner Marc M Singer Harold A HA Matrougui Khalid K Barroso Margarida M Romanin Christoph C Trebak Mohamed M

Circulation research 20130124 7

<h4>Rationale</h4>Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store-operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown.<h4>Objective</h4>The goal of this study was to dete ...[more]

PMID: 23349245

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Project description:Key pointsTemporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca2+ signalling in many aspects of epilepsy but the diversity of Ca2+ channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca2+ channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures.AbstractStore-operated Orai1 channels are a major mechanism for Ca2+ entry in many cells and mediate numerous functions including gene expression, cytokine production and gliotransmitter release. Orai1 is expressed in many regions of the mammalian brain; however, its role in regulating neuronal excitability, synaptic function and brain disorders has only now begun to be investigated. To investigate a potential role of Orai1 channels in status epilepticus induced by chemoconvulsants, we examined acute seizures evoked by intraperitoneal injections of kainic acid (KA) and pilocarpine in mice with a conditional deletion of Orai1 (or its activator STIM1) in the brain. Brain-specific Orai1 and STIM1 knockout (KO) mice exhibited significantly stronger seizures (P = 0.00003 and P < 0.00001), and higher chemoconvulsant-induced mortality (P = 0.02) compared with wildtype (WT) littermates. Electrophysiological recordings in hippocampal brain slices revealed that KA stimulated the activity of inhibitory interneurons in the CA1 hippocampus (P = 0.04) which failed to occur in Orai1 KO mice. Further, KA and pilocarpine increased the frequency of spontaneous IPSCs in CA1 pyramidal neurons >twofold (KA: P = 0.04; pilocarpine: P = 0.0002) which was abolished in Orai1 KO mice. Mice with selective deletion of Orai1 in GABAergic neurons alone also showed stronger seizures to KA (P = 0.001) and pilocarpine (P < 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.

Dataset Information

Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia.

Publications

Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia.

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