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

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 S1...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-04, Vol.22 (8), p.4082
Main Authors: Zhemkov, Vladimir, Geva, Michal, Hayden, Michael R, Bezprozvanny, Ilya
Format: Article
Language:English
Subjects:
Agonists
Alzheimer's disease
Amyotrophic lateral sclerosis
Animals
Ascorbic acid
Binding sites
Cholesterol
Cholesterol - metabolism
Communication
contact sites
Endoplasmic reticulum
Gene Ontology
HeLa Cells
Humans
Hypotheses
Investigations
Ion channels
L-Ascorbate peroxidase
Ligands
Lipids
Localization
Membrane Microdomains - metabolism
Mitochondria
Molecular Targeted Therapy
Mutation
Narcotics
neurodegeneration
Neurodegenerative Diseases - metabolism
Neurological disorders
Peroxidase
Physiology
Plasma
Proteins
Receptors, sigma - metabolism
Regulation
Sigma-1 Receptor
Sterols
Trophic factors
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22084082