Moderator of 1 Session
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SIGMA-1 RECEPTOR – A ROLE IN NEURONAL SIGNALING AND NEURODEGENERATION
Abstract
Aims
The sigma 1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. Agonists of S1R demonstrated neuroprotective effects in preclinical models and there are several on-going clinical trials of S1R agonists in neurodegenerative disorders. However, signaling functions of S1R are poorly understood. We set out to test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol
Methods
Biophysical experiemnts with in vitro reconstitution systems, experiments with neuronal and cellular cultures
Results
By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. Further, we found that S1R agonists cause disruption of S1R clusters. Based on these results we propose that 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 APEX technology
Conclusions
We proposed 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 mechanism may explain neuroprotective and synaptoprotective effects of S1R agonists in Alzheimer's disease and other neurodegenerative disorders.