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S-Nitrosylation of STIM1 by Neuronal Nitric Oxide Synthase Inhibits Store-Operated Ca2+ Entry
Le Gui1, Jinhui Zhu2, Xiangru Lu2
1Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Institute of Cardiovascular Disease, Nantong University, Nantong, Jiangsu, China.
Journal of Molecular Biology
|April 30, 2018
Summary
Nitric oxide (NO) inhibits store-operated calcium entry (SOCE) by S-nitrosylating stromal interacting molecule-1 (STIM1). This modification stabilizes STIM1, preventing its oligomerization and subsequent calcium channel activation in cardiomyocytes.
Area of Science:
- Cellular Physiology
- Molecular Biology
- Cardiovascular Research
Background:
- Store-operated calcium entry (SOCE) is crucial for cellular calcium homeostasis, mediated by STIM1 and Orai1.
- Nitric oxide (NO) signaling is vital in cardiovascular function, but its direct impact on SOCE components like STIM1 remains unclear.
- Neuronal NO synthase (nNOS) is localized to the sarcoplasmic reticulum in cardiomyocytes.
Purpose of the Study:
- To investigate the effect of nitric oxide (NO) on the function of stromal interacting molecule-1 (STIM1) in regulating store-operated calcium entry (SOCE).
- To determine the molecular mechanism by which NO influences STIM1 activity and its role in cardiomyocytes.
Main Methods:
- S-nitrosylation assays to detect NO modification of STIM1.
- Electrophysiology (measuring ICRAC) to assess SOCE activity in cardiomyocytes and HEK293 cells.
- Confocal microscopy to observe STIM1 puncta formation and oligomerization.
- Site-directed mutagenesis (Cys49Ser/Cys56Ser STIM1) to identify key nitrosylation sites.
- Biophysical techniques (thermal stability, protein backbone mobility) to analyze STIM1 structural changes.
Main Results:
- STIM1 is susceptible to S-nitrosylation by NO.
- Inhibition or deficiency of neuronal NO synthase enhances SOCE and ICRAC in cardiomyocytes.
- NO donors inhibit STIM1 oligomerization and SOCE in HEK293 cells, an effect dependent on Cys49 and Cys56 of STIM1.
- NO-induced S-nitrosylation of Cys49 and Cys56 stabilizes the STIM1 luminal domain, reducing protein backbone mobility and suppressing calcium depletion-induced oligomerization.
Conclusions:
- S-nitrosylation of STIM1 by NO acts as a negative regulator of SOCE.
- NO-mediated stabilization of the STIM1 luminal domain inhibits its oligomerization and subsequent activation of calcium channels.
- This NO-STIM1 interaction provides a novel mechanism for controlling calcium influx in cardiomyocytes and other cell types.
Keywords:
S-nitrosylationneuronal nitric oxide synthasenitric oxidestore-operated calcium entrystromal interaction molecule-1More Related Videos
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