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Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

1
Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA
2
Prilenia Therapeutics Development LTD, Herzliya 4673304, Israel
3
Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, BC V6H 3V5, Canada
4
Laboratory of Molecular Neurodegeneration, Peter the Great St Petersburg State Polytechnic University, 195251 St. Petersburg, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Carmen Abate
Int. J. Mol. Sci. 2021, 22(8), 4082; https://doi.org/10.3390/ijms22084082
Received: 25 March 2021 / Revised: 9 April 2021 / Accepted: 13 April 2021 / Published: 15 April 2021
The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems. View Full-Text
Keywords: sigma-1 receptor; endoplasmic reticulum; mitochondria; contact sites; cholesterol; neurodegeneration; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; drug target sigma-1 receptor; endoplasmic reticulum; mitochondria; contact sites; cholesterol; neurodegeneration; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; drug target
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MDPI and ACS Style

Zhemkov, V.; Geva, M.; Hayden, M.R.; Bezprozvanny, I. Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases. Int. J. Mol. Sci. 2021, 22, 4082. https://doi.org/10.3390/ijms22084082

AMA Style

Zhemkov V, Geva M, Hayden MR, Bezprozvanny I. Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2021; 22(8):4082. https://doi.org/10.3390/ijms22084082

Chicago/Turabian Style

Zhemkov, Vladimir, Michal Geva, Michael R. Hayden, and Ilya Bezprozvanny. 2021. "Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases" International Journal of Molecular Sciences 22, no. 8: 4082. https://doi.org/10.3390/ijms22084082

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