Sigma-2 Receptor-Mediated Changes in Metabolism and Calcium Signaling

McVeigh, Bridget McVeigh

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Year:: 2019
Contributor:: McVeigh, Bridget McVeigh (creator); Bowen, Wayne (Advisor); Oancea, Elena (Reader); Marshall, John (Reader); Brown University. Department of Molecular Pharmacology, Physiology and Biotechnology (sponsor)
Genre:: theses
Subject:: Metabolism; Cancer; Calcium
Extent:: iv, 37 p.
DOI: https://doi.org/10.26300/29hh-7544

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Abstract:: Abstract of Sigma-2 Receptor-Mediated Changes in Metabolism and Calcium Signaling, Degree ScM, Brown University, May 2019 Sigma receptors are a pharmacologically distinct family of membrane-bound orphan receptors, which are classified into two subtypes: sigma-1 and sigma-2. Sigma-2 receptors, recently identified as TMEM97, are overexpressed in cancer cells compared to normal cells. Previous studies showed that sigma-2 receptor ligands activate a bifurcating pathway in these cells: programmed cellular death and metabolic stimulation. The metabolic arm of the pathway is characterized by an increase in reduction of MTT, an increase in cellular ATP and NAD/NADH levels, and a stabilization of HIF-1a. Evidence suggests that calcium signaling may also be involved. The present study investigated the metabolic effects of several sigma-2 receptor ligands that are analogs of the sigma-2 antagonist, SN79. Effects of these compounds on intracellular calcium release were also examined. Treatment of human SK-N-SH neuroblastoma cells with CM764, CM571, and WA504 for various time points resulted in dose-dependent reduction of MTT. The metabolic effect was found to develop only after 3 to 6 hours of treatment. Furthermore, CM764 and CM571 produced an immediate, robust, and transient rise in cytosolic calcium. Using thapsigargin pretreatment, the intracellular calcium source was identified as the endoplasmic reticulum. It is hypothesized that this robust calcium release is linked to the sigma-2 receptor-induced metabolic stimulative effect. As Supplementary Material, a series of six norbenzomorphan ligands with high sigma-2R affinity and good selectivity over sigma-1R were also examined for effects of MTT reduction. Four of these compounds (SAS-1129, UKH-1114, DKR-1516, SFM-1601) had a biphasic effect on MTT reduction, producing metabolic stimulation at lower doses and inducing cell death (decreased MTT reduction) at higher doses. Two of the compounds (DKR-1051 and SFM-1615) produced cell death at all doses, without evidence of metabolic stimulation.
Notes:: Thesis (Sc. M.)--Brown University, 2019

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McVeigh, Bridget McVeigh, "Sigma-2 Receptor-Mediated Changes in Metabolism and Calcium Signaling" (2019). Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.26300/29hh-7544

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Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations

Theses and Dissertations for the Molecular Pharmacology, Physiology, and Biotechnology department.
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