Store-operated calcium entry is present in HL-1 cardiomyocytes and contributes to resting calcium

Touchberry, Chad D.; Elmore, Chris J.; Nguyen, Thanh Dang; Andresen, Jon; Zhao, Xiaoli; Orange, Matthew; Weisleder, Noah; Brotto, Marco; Claycomb, William C.; Wacker, Michael

doi:10.1016/j.bbrc.2011.10.133

Cited by 50 publications

(43 citation statements)

References 30 publications

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“…Inhibitors such as SKF-96365, 2-aminoethoxydiphenyl borate (14), and spider venom GsMTx-4 (15) are nonselective. Pyr3 (ethyl-1-(4-(2,3,3-trichloro-acryl-amide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate) has been identified as a selective TRPC3 antagonist (16,17), although members of the 5-(trifluoro-methyl)-1H-pyrazole family to which it belongs block Ca 2+ release-activated calcium (CRAC) channels, such as Orai channels (18,19).…”

Section: Significancementioning

confidence: 99%

Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Seo

Rainer

Hahn

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

171

163

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Significance Cardiac hypertrophy and dysfunction in response to sustained hormonal and mechanical stress are sentinel features of most forms of heart disease. Activation of non–voltage-gated transient receptor potential canonical channels TRPC3 and TRPC6 may contribute to this pathophysiology and provide a therapeutic target. Effects from combined selective inhibition have not been tested previously. Here we report the capability of highly selective TRPC3/6 inhibitors to block pathological hypertrophic signaling in several cell types, including adult cardiac myocytes. We show in vivo redundancy of each channel; individual gene deletion was not protective against sustained pressure overload, whereas combined deletion ameliorated the response. These data strongly support a role for both channels in cardiac disease and the utility of selective combined inhibition.

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Section: Significancementioning

confidence: 99%

Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Seo

Rainer

Hahn

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

171

163

View full text Add to dashboard Cite

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“…It is also increasingly apparent that STIM1 has functions that are independent of SOCE, including regulation of ARC channels (36) and maintenance of ER/SR function (11). While there has been a growing body of evidence demonstrating that STIM1 is present in cardiomyocytes (19,22,37,44), particularly as a mediator of cardiac hypertrophy (13,17,22,38), the physiological role of STIM1 in the adult heart remains poorly understood. We have demonstrated for the first time that STIM1 plays an essential role in maintaining cardiomyocyte homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, at 20 wk of age, even though functionally there were no differences between groups, there were increased inflammatory infiltrate and cardiac fibrosis in cr STIM1-KO hearts, indicative of additional cardiomyocyte stress and injury. While much of the focus on the role of STIM1 as a key mediator of SOCE and Ca 2ϩ signaling, it has also been suggested that STIM1 may play a critical role in regulating ER/SR function to ensure appropriate folding and processing of proteins (37). This is supported by the fact that as early as 12 wk of age, there is a significant elevation in CHOP and PDI proteins in cr STIM1-KO hearts, which persists up to 36 wk of age.…”

Section: Discussionmentioning

confidence: 99%

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Collins

Zou

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Young ME, Marchase RB, Chatham JC. Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function. Am J Physiol Heart Circ Physiol 306: H1231-H1239, 2014. First published February 28, 2014 doi:10.1152/ajpheart.00075.2014.-The endoplasmic reticulum (ER) Ca 2ϩ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca 2ϩ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ( cr STIM1-KO) mouse. In cardiomyocytes isolated from cr STIM1-KO mice, STIM1 expression was reduced by ϳ92% with no change in the expression of related store-operated Ca 2ϩ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that cr STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in cr S-TIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in cr STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in cr STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function. store-operated Ca 2ϩ entry; STIM1; cardiomyocytes; ER stress; mitochondria

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“…Li et al (51) reported that Junctophilin knockout myotubes had reduced SOCE, decreased STIM1, Orai1, and TRPC1/3 protein expression as well as lower basal Ca 2ϩ levels compared with wild-type cells. Furthermore, in HL-1 cells knockdown of Orai1 decreased SOCE as well as both cytosolic and SR Ca 2ϩ levels (120). In addition, binding of STIM1 to LTCC has been shown to inhibit these channels (87,133).…”

Section: Orai1/trpcmentioning

confidence: 95%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

111

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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Store-operated calcium entry is present in HL-1 cardiomyocytes and contributes to resting calcium

Cited by 50 publications

References 30 publications

Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

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