Abstract
ABSTRACTStore-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.
Highlights
Cardiomyopathies are a major cause of morbidity and mortality throughout the western world, with current treatment options limited to palliative pharmacological or invasive therapy (McKenna et al, 2017)
The critical importance of proper Ca2+ homeostasis and transport in cardiomyocytes is accentuated by the fact that most cardiomyopathies involve Ca2+ dysregulation
Clear understanding of the cellular and molecular mechanisms that regulate cardiomyocyte Ca2+ handling is fundamental to unraveling the complexities of cardiac pathophysiology
Summary
Cardiomyopathies are a major cause of morbidity and mortality throughout the western world, with current treatment options limited to palliative pharmacological or invasive therapy (McKenna et al, 2017). Irregularities in cardiomyocyte calcium (Ca2+) homeostasis are a major contributing factor to cardiomyopathy and heart failure pathogenesis, and targeting Ca2+ signaling mechanisms may. The role of Ca2+ in the process of excitation-contraction (E-C) coupling, which drives cardiomyocyte contractility, is well established. Store-operated Ca2+ entry (SOCE) is a process that plays a major role in maintaining cellular Ca2+ homeostasis, as it couples the influx of extracellular Ca2+ to the depletion of sarco/endoplasmic (S/ER) Ca2+ stores. Despite the prominent role for SR Ca2+ stores in cardiomyocyte physiology, the functions of SOCE in cardiomyocytes and overall cardiac physiology are poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
