期刊
CELL REPORTS
卷 35, 期 4, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109040
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资金
- National Institute on Drug Abuse (NIDA)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- National Center for Advancing Translational Sciences (NCATS)
- National Institutes of Health/NIDDK [DK112921, DK020579]
- National Institutes of Health/NCATS [TR002065, TR000448]
The study identifies several clinically used drugs, including bromocriptine, that can prevent the redistribution of ER proteins under pathological conditions. These drugs exhibit protective effects in cell-based models and in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity also show efficacy in stabilizing the ER proteome, suggesting a non-canonical mechanism of action.
Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.
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