Emergence of Orai3 activity during cardiac hypertrophy

Saliba, Youakim; Keck, Mathilde; Marchand, Alexandre; Atassi, Fabrice; Ouillé, Aude; Cazorla, Olivier; Trebak, Mohamed; Pavoine, Catherine; Lacampagne, Alain; Hulot, Jean‐Sébastien; Farès, Nassim; Fauconnier, Jérémy; Lompré, Anne Marie

doi:10.1093/cvr/cvu207

Cited by 39 publications

(48 citation statements)

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“…Finally, previous reports have shown that STIM1 activates in response to a mechanical or humoral hypertrophic stressor, which allows gating with plasma membrane Orai channels 9 . We thus sought to determine whether inhibition of STIM1/Orai complex at the plasma membrane reproduces the effects on mTORC2/Akt activation observed after Stim1 silencing.…”

Section: Resultsmentioning

confidence: 77%

“…Intriguingly, modifications in Akt Ser473 phosphorylation were observed in skeletal muscle from Stim1 -deficient mice 47 and in arterial smooth muscle cells after Orai3 knockdown 48 thus asking whether the STIM1/Akt coupling is specifically observed in muscular cells. We and others have previously shown that in cardiac myocytes, as well as in smooth muscle cells, STIM1 co-immunoprecipitates with Orai1 and 3 channels under resting conditions 9, 49 . STIM1 might thus represent a large protein complex that can adapt to different stresses to interact with a diversity of complexes 12 .…”

Section: Discussionmentioning

confidence: 72%

“…STIM1 might thus represent a large protein complex that can adapt to different stresses to interact with a diversity of complexes 12 . In response to hypertrophic or proliferative stimulus, a large recruitment of Orai3 to STIM1 and Orai1 occurs thus allowing for a store-independent entry 9, 49 . This contrasts with the hypothetical model in immune cells where calcium store depletion triggers STIM1 binding and activation of plasma membrane channels including Orai1 8 .…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that an interaction between STIM1 and two members of the Orai family, i.e. Orai1 and Orai3 channels, occurs in response to hypertrophic stimulation and sustain the emergence of this alternative mechanism of Ca 2+ entry 9 . A similar phenomenon has been reported in proliferative smooth muscle cells where STIM1 controls heteromultimers of Orai1 and Orai3 that are regulated by leucotrienes C4 9-11 .…”

mentioning

confidence: 99%

“…Orai1 and Orai3 channels, occurs in response to hypertrophic stimulation and sustain the emergence of this alternative mechanism of Ca 2+ entry 9 . A similar phenomenon has been reported in proliferative smooth muscle cells where STIM1 controls heteromultimers of Orai1 and Orai3 that are regulated by leucotrienes C4 9-11 . Interactions with less Ca 2+ selective channels, such as TRPCs, have also been suggested and STIM1 overexpression leads to dysregulated calcium transients 5, 12 .…”

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confidence: 99%

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Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Bénard

Cacheux

et al. 2016

Circulation

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Background STromal Interaction Molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiac myocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma but the pathways underpinning this effect have not been examined. Methods and Results To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiac myocytes using in vivo gene delivery of specific short hairpin RNAs. In three different models, we found that Stim1 silencing prevents the development of pressure-overload induced hypertrophy but also reverses pre-established cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the anti-hypertrophic and pro-apoptotic GSK-3β molecule. Pharmacological inhibition of GSK-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of AktS473, a hydrophic motif of Akt that is directly phosphorylated by mTORC2. We found that Stim1 silencing directly impaired mTORC2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTORC2 complex. Conclusions These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiac myocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2 (mTORC2), which further results in repression of GSK-3β activity.

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Section: Resultsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Bénard

Cacheux

et al. 2016

Circulation

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Proteins Interacting with STIM1 and Store-Operated Ca2+ Entry

Wang

Demaurex

2021

Cellular Biology of the Endoplasmic Reticulum

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Tissue Specificity: Store-Operated Ca2+ Entry in Cardiac Myocytes

Bootman

Rietdorf

2017

Advances in Experimental Medicine and Biology

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Calcium (Ca) is a key regulator of cardiomyocyte contraction. The Ca channels, pumps, and exchangers responsible for the cyclical cytosolic Ca signals that underlie contraction are well known. In addition to those Ca signaling components responsible for contraction, it has been proposed that cardiomyocytes express channels that promote the influx of Ca from the extracellular milieu to the cytosol in response to depletion of intracellular Ca stores. With non-excitable cells, this store-operated Ca entry (SOCE) is usually easily demonstrated and is essential for prolonging cellular Ca signaling and for refilling depleted Ca stores. The role of SOCE in cardiomyocytes, however, is rather more elusive. While there is published evidence for increased Ca influx into cardiomyocytes following Ca store depletion, it has not been universally observed. Moreover, SOCE appears to be prominent in embryonic cardiomyocytes but declines with postnatal development. In contrast, there is overwhelming evidence that the molecular components of SOCE (e.g., STIM, Orai, and TRPC proteins) are expressed in cardiomyocytes from embryo to adult. Moreover, these proteins have been shown to contribute to disease conditions such as pathological hypertrophy, and reducing their expression can attenuate hypertrophic growth. It is plausible that SOCE might underlie Ca influx into cardiomyocytes and may have important signaling functions perhaps by activating local Ca-sensitive processes. However, the STIM, Orai, and TRPC proteins appear to cooperate with multiple protein partners in signaling complexes. It is therefore possible that some of their signaling activities are not mediated by Ca influx signals, but by protein-protein interactions.

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Emergence of Orai3 activity during cardiac hypertrophy

Abstract: Cardiac Orai3 is the essential partner of STIM1 and drives voltage-independent Ca(2+) entries in adult cardiomyocytes. Arachidonic acid-activated currents, which are supported by Orai3, are present in adult cardiomyocytes and increased during hypertrophy.

Cited by 39 publications

References 44 publications

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Proteins Interacting with STIM1 and Store-Operated Ca2+ Entry

Tissue Specificity: Store-Operated Ca2+ Entry in Cardiac Myocytes

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