Identification of select G-protein coupled receptors as regulators of the ER-mitochondria contact by drug screening
biorxiv(2020)
摘要
Endoplasmic reticulum-mitochondrial (ER-Mito) contacts are crucial for many cellular functions. Their dysregulation has been implicated in many disorders including neurodegenerative, cardiovascular and metabolic diseases, and cancer. However, little is known about the regulatory pathways of ER-Mito contacts. To uncover such pathways, we screened a drug library for the ER-Mito contact modulators using a split-luciferase reassembly assay. We identified multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, in our screen. Using multiple independent assays, we validated that these drugs enhance the physical and functional interactions between ER and mitochondria. Our data provide evidence that cytoplasmic calcium plays a role in drug-induced ER-Mito coupling. Together our study identifies GPCR activation as a novel regulatory mechanism of ER-Mito contacts and highlights the role of these contacts in responding to physiological demands or stresses. Furthermore, our findings reveal a new mechanism of action for β-AR agonists in multiple diseases.
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关键词
β,-adrenergic receptors (β,-ARs),β,-AR agonists,calcium,cAMP,endoplasmic reticulum-mitochondria contact,drug screen,G-protein coupled receptors (GPCRs),GPCR agonists,split-Rluc reassembly assay
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