Sigma1 Receptor Inhibits TRPC1-Mediated Ca 2+ Entry That Promotes Dopaminergic Cell Death
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ORIGINAL RESEARCH
Sigma1 Receptor Inhibits TRPC1‑Mediated Ca2+ Entry That Promotes Dopaminergic Cell Death Yuyang Sun1 · Pramod Sukumaran1 · Brij B. Singh1 Received: 14 April 2020 / Accepted: 28 May 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Regulation of Ca2+ homeostasis is essential for neuronal function and its survival. Recent data suggest that TRPC1 function as the endogenous store-mediated C a2+ entry channel in dopaminergic cells, and loss of TRPC1 function leads to neurodegeneration; however, its regulation is not fully identified. Here we provide evidence that the sigma 1 receptor contributes to the loss of dopaminergic cells by blocking TRPC1-mediated Ca2+ entry. Importantly, downregulation of sigma 1 receptor expression significantly decreased neurotoxin-induced loss of dopaminergic cells as measured by MTT assays and caspase activity was also inhibited. Importantly, sigma 1 receptor inhibited TRPC1-mediated Ca2+ entry and silencing of sigma 1 receptor significantly restored store-dependent C a2+ influx. Although co-immunoprecipitation failed to show an interaction between the TRPC1 and sigma 1 receptor, store depletion promoted a decrease in the sigma 1 receptor-STIM1 association. Neurotoxin-induced loss of C a2+ entry was significantly restored in cells that had decreased sigma 1 receptor expression. Furthermore, TRPC1 or STIM1 silencing inhibited store-mediated C a2+ entry, which was further increased upon the downregulation of the sigma 1 receptor expression. TRPC1 silencing prevented the increased neuroprotection and caspase activity observed upon the downregulation of sigma 1 receptor. Finally, sigma 1 receptor activation also significantly decreased TRPC1-mediated C a2+ entry and lead to an increase in neurodegeneration. In contrast, addition of sigma 1 receptor antagonist prevented neurotoxin-induced neurodegeneration and facilitated TRPC1-mediated C a2+ influx. Together 2+ these results suggest that the sigma 1 receptor is involved in the inhibition of TRPC1- mediated Ca entry, which leads to the degeneration in the dopaminergic cells, and prevention of sigma 1 receptor function could protect neuronal cell death as observed in Parkinson’s disease. Keywords TRPC1 · Sigma1 receptor · Ca2+ homeostasis · Cell death · And neurodegeneration Abbreviations [Ca2+]i Intracellular free calcium concentration or cytoplasmic free calcium concentration ER Endoplasmic reticulum HBSS Hank’s balanced salt solution MPTP/MPP+ 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine/1-methyl-4-phenylpyridinium ions ORAI Calcium release-activated calcium channel protein PBS Phosphate-buffered saline PD Parkinson’s disease PM Plasma membrane * Brij B. Singh [email protected] 1
Department of Periodontics, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
SERCA Sacro/endoplasmic reticulum Ca2+-ATPase σ1R Sigma 1 receptor SOCE Store-operated calcium entry SOCC Store-operated Ca2+ entry channels STIM1 Stromal interac
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