SOCE and STIM1 signaling in the heart: Timing and location matter

Rosenberg, Paul B.; Katz, Danielle A.; Bryson, Victoria

doi:10.1016/j.ceca.2018.11.008

Cited by 22 publications

(20 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Paradoxically, it is still unknown whether loss-of-function mutations in Stim1 or Orai1 result in heart defects or cardiomyopathies in humans. This is likely due to the fact that individuals homozygous for these mutations die from immunodeficiency in infancy or early childhood, before adverse heart phenotypes may fully manifest (Rosenberg et al, 2019). Therefore, animal model studies, including powerful genetic screens and in vivo analyses in Drosophila, will continue to be vital to our understanding of how alterations to SOCE result in or contribute to devastating cardiomyopathies and heart failure.…”

Section: Research Articlementioning

confidence: 99%

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

2020

View full text Add to dashboard Cite

Store-operated Ca2+ entry (SOCE) is an essential Ca2+ signaling mechanism present in most animal cells. SOCE refers to Ca2+ influx that is activated by depletion of sarco/endoplasmic reticulum (S/ER) Ca2+ stores. The main components of SOCE are STIM and Orai. STIM proteins function as S/ER Ca2+ sensors, and upon S/ER Ca2+ depletion STIM rearranges to S/ER-plasma membrane junctions and activates Orai Ca2+ influx channels. Studies have implicated SOCE in cardiac hypertrophy pathogenesis, but SOCE's role in normal heart physiology remains poorly understood. We therefore analyzed heart-specific SOCE function in Drosophila, a powerful animal model of cardiac physiology. We show that heart-specific suppression of Stim and Orai in larvae and adults resulted in reduced contractility consistent with dilated cardiomyopathy. Myofibers were also highly disorganized in Stim and Orai RNAi hearts, reflecting possible decompensation or upregulated stress signaling. Furthermore, we show that reduced heart function due to SOCE suppression adversely affected animal viability, as heart specific Stim and Orai RNAi animals exhibited significant delays in post-embryonic development and adults died earlier than controls. Collectively, our results demonstrate that SOCE is essential for physiological heart function, and establish Drosophila as an important model for understanding the role of SOCE in cardiac pathophysiology.

show abstract

Section: Research Articlementioning

confidence: 99%

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

2020

View full text Add to dashboard Cite

show abstract

“…The molecular components of CRAC channels consist of the pore-forming subunit Orai (Orai1, Orai2, and Orai3), and the Ca 2+ release-sensing subunit STIM (STIM1 and STIM2). The role of Orai/STIM in cardiac myocytes and cardiac function has been extensively studied [120][121][122][123]. However, controversial results have been reported regarding the contribution of Orai/STIM to cardiac physiology and pathology [120,124].…”

Section: Ca 2+ Entry Through Crac (Orai/stim) Channels In Cardiac Fibmentioning

confidence: 99%

“…The role of Orai/STIM in cardiac myocytes and cardiac function has been extensively studied [120][121][122][123]. However, controversial results have been reported regarding the contribution of Orai/STIM to cardiac physiology and pathology [120,124]. In fibroblasts, although the Orai and STIM subunits have been detected by qPCR or RT-PCR in mouse and human cardiac fibroblasts [37,46], CRAC currents have not been recorded by patch-clamp [37].…”

Section: Ca 2+ Entry Through Crac (Orai/stim) Channels In Cardiac Fibmentioning

confidence: 99%

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

View full text Add to dashboard Cite

Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca2+ signaling plays a vital role in this pathological process, what contributes to Ca2+ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca2+ signaling. Intracellular Ca2+ signals are generated by Ca2+ release from intracellular Ca2+ stores and by Ca2+ entry through a multitude of Ca2+-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca2+ signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca2+-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca2+ signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca2+-permeable channels play in cardiac fibrosis.

show abstract

“…In conclusion, our results demonstrate that SOCE mediated by STIM and Orai is essential for proper function of the Drosophila heart, and add to a growing number of studies that collectively suggest that SOCE has highly conserved functional roles in cardiomyocytes across animal species. Paradoxically, it is still unknown whether loss of function mutations in STIM1 or Orai1 result in heart defects or cardiomyopathies in humans likely due to the fact that individuals homozygous for these mutations die from immunodeficiency in infancy or early childhood, before adverse heart phenotypes may fully manifest (Rosenberg et al, 2019). Therefore, animal model studies will continue to be vital to our understanding of how alterations to SOCE result in or contribute to devastating cardiomyopathies and heart failure.…”

Section: Discussionmentioning

confidence: 99%

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

Petersen

Wolf

Smyth

2019

Preprint

View full text Add to dashboard Cite

Store-operated Ca 2+ entry (SOCE) is an essential Ca 2+ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca 2+ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca 2+ stores. In the SOCE pathway, STIM proteins function as Ca 2+ sensors in the ER, and upon ER Ca 2+ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca 2+ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca 2+ homeostasis.Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in postembryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establishDrosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.

show abstract

SOCE and STIM1 signaling in the heart: Timing and location matter

Cited by 22 publications

References 107 publications

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

Contact Info

Product

Resources

About