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Exploring the role of GPRC6A in regulating mTORC1 signaling and tau metabolism
Poster Title: Exploring the role of GPRC6A in regulating mTORC1 signaling and tau metabolism
Submitted on 09 Feb 2018
Author(s): John Calahatian, Chao Ma MS, Mani Kallupurackal, Huimin Liang MS, Miles Nowicki, Emily Lopez, Daniel Lee PhD
Affiliations: University of South Florida
This poster was presented at USF Research Day 2018
Poster Views: 768
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Poster Information
Abstract: A unique interaction between L-arginine metabolism and tau metabolism was shown in previous data. A depletion of L-arginine due to overexpressing the metabolizing enzyme arginase 1(Arg1) and arginine deiminase(ADI) significantly reduced tau pathology in transgenic mouse models. We speculate that these effects are associated with increased autophagy through an amino acid sensing mechanism. G protein coupled receptor family C, group 6 member A(GPRC6A) was recently deorphanized by binding to basic L-α amino acids, such as L-arginine and L-ornithine. We hypothesize that GPRC6A serves as an extracellular arginine sensor and decreased GPRC6A signaling lead to inhibition of mTORC1 signaling pathway, thus activates autophagy and promotes tau clearance.We utilized genetically designed shRNA/siRNA to downregulate GPRC6A expression in both mouse naïve neuronal cell line and neuronal tauopathy cell line overexpressing human wild type tau. We quantitatively measured the protein levels of several key mTORC1 downstream markers and tau through western blotting. We found the GPRC6A shRNA/siRNA successfully downregulated GPRC6A expression, significantly reduced the mTORC1 substrates, activated putative markers of autophagy and decreased tau expression in vitro.Overall, this is the first study to show that GPRC6A is linked to mTORC1 signaling and modulation of this receptor can reduce tau levels in a neuronal cell line stably overexpressing tau. Further animal studies are required to warrant the elucidation for the role of GPRC6A in modulating tau metabolism in tau transgenic mice. Therefore, GPRC6A may serve as a novel therapeutic target to treat tauopathies.Summary: Downregulation of arginine sensor GPRC6A modulates mTORC1 signaling and reduces their expression, activated putative markers of autophagy, and decreased tau expression in vitro in mouse naive neuronal cells.References: Amino acid regulation of autophagy through the GPCR TAS1R1-TAS1R3 Wauson E.M. et al. Autophagy. 9(3):418-9 (2013))Report abuse »
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