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bioRxiv · 10.1101/304022

S-Nitrosylation of STIM1 by neuronal nitric oxide synthase inhibits store-operated Ca2+ entry

Gui, L.·Zhu, J.·Lu, X.·Sims, S. M.·Lu, W.-Y.·Stathopulos, P. B.·Feng, Q.
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Abstract

Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule-1 (STIM1) and Orai1 represents a major route of Ca2+ entry in mammalian cells and is initiated by STIM1 oligomerization in the endoplasmic or sarcoplasmic reticulum (ER/SR). However, the effects of nitric oxide (NO) on STIM1 function are unknown. Neuronal NO synthase (nNOS) is located in the SR of cardiomyocytes. Here, we show that STIM1 is susceptible to S-nitrosylation. nNOS deficiency or inhibition enhanced Ca2+ release-activated Ca2+ channel current (ICRAC) and SOCE in cardiomyocytes. Consistently, NO donor S-nitrosoglutathione (GSNO) inhibited STIM1 puncta formation and ICRAC in HEK293 cells, but this effect was absent in cells expressing the Cys49Ser/Cys56Ser STIM1 double mutant. Furthermore, NO donors caused Cys49 and Cys56-specific structural changes associated with reduced protein backbone mobility, increased thermal stability and suppressed Ca2+-depletion-dependent oligomerization of the luminal Ca2+-sensing region of STIM1. Collectively, our data show that S-nitrosylation of STIM1 suppresses oligomerization via enhanced luminal domain stability and rigidity, and inhibits SOCE in cardiomyocytes.

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Gui, L., Zhu, J., Lu, X., Sims, S. M., Lu, W.-Y., Stathopulos, P. B., Feng, Q.. 2018-04-18. S-Nitrosylation of STIM1 by neuronal nitric oxide synthase inhibits store-operated Ca2+ entry. https://doi.org/10.1101/304022

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