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Sigma1 Receptor Inhibits TRPC1-Mediated Ca2+ Entry That Promotes Dopaminergic Cell Death

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Abstract

Regulation of Ca2+ homeostasis is essential for neuronal function and its survival. Recent data suggest that TRPC1 function as the endogenous store-mediated Ca2+ 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 Ca2+ 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 Ca2+ entry was significantly restored in cells that had decreased sigma 1 receptor expression. Furthermore, TRPC1 or STIM1 silencing inhibited store-mediated Ca2+ 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 Ca2+ entry and lead to an increase in neurodegeneration. In contrast, addition of sigma 1 receptor antagonist prevented neurotoxin-induced neurodegeneration and facilitated TRPC1-mediated Ca2+ influx. Together these results suggest that the sigma 1 receptor is involved in the inhibition of TRPC1- mediated Ca2+ 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.

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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-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium ions

ORAI:

Calcium release-activated calcium channel protein

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

PM:

Plasma membrane

SERCA:

Sacro/endoplasmic reticulum Ca2+-ATPase

σ1R:

Sigma 1 receptor

SOCE:

Store-operated calcium entry

SOCC:

Store-operated Ca2+ entry channels

STIM1:

Stromal interaction molecule 1

Tg:

Thapsigargin

TRPC1:

Transient receptor potential canonical channel 1

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Acknowledgements

This work was partially funded by grant support from Perry and Ruby Stevens PD Center of Excellence at UT Health San Antonio, which was awarded to B.B.S. The funders do not have a role in study design, data analysis, and/or interpretation of the data.

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Authors and Affiliations

  1. Department of Periodontics, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA

    Yuyang Sun, Pramod Sukumaran & Brij B. Singh

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  1. Yuyang Sun
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  2. Pramod Sukumaran
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  3. Brij B. Singh
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BBS designed the studies that were performed by YS and PS. The paper was written by YS and BBS. All authors reviewed the results and approved the final manuscript.

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Correspondence to Brij B. Singh.

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Sun, Y., Sukumaran, P. & Singh, B.B. Sigma1 Receptor Inhibits TRPC1-Mediated Ca2+ Entry That Promotes Dopaminergic Cell Death. Cell Mol Neurobiol 41, 1245–1255 (2021). https://doi.org/10.1007/s10571-020-00892-5

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