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Title: GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea

Abstract

1 Scope: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood.2 Methods and results: We found that GPRC6A, a multi-ligand-sensing G-protein-coupled receptor that regulates energy metabolism, sex hormone production, and prostate cancer progression, is a target for gallates. Sodium gallate (SG), gallic acid (GA) > ethyl gallate (EG) > octyl gallate (OG) dose dependently activated ERK in HEK-293 cells transfected with GPRC6A but not in non-transfected controls. SG also stimulated insulin secretion in β-cells isolated from wild-type mice similar to the endogenous GPRC6A ligands, osteocalcin (Ocn) and testosterone (T). Side-chain additions to create OG resulted in loss of GPRC6A agonist activity. Another component of green tea, epigallocatechin 3-gallate (EGCG), dose-dependently inhibited Ocn activation of GPRC6A in HEK-293 cells transfected with GPRC6A and blocked the effect of Ocn in stimulating glucose production in CH10T1/2 cells. Using structural models of the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A, calculations suggest that l-amino acids and GA bind to the VFT, whereas EGCG is calculated to bind to sites in both the VFT and 7-TM.3 In conclusion, GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effectmore » of green tea consumption.« less

Authors:
 [1];  [2];  [1];  [3];  [3];  [1]
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Medicine
  2. Univ. of Tennessee, Knoxville, TN (United States). UT/ORNL Center for Molecular Biophysics
  3. Univ. of Tennessee, Knoxville, TN (United States). UT/ORNL Center for Molecular Biophysics and Dept. of Biochemistry and Cellular and Molecular Biology
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1459287
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecular Nutrition & Food Research
Additional Journal Information:
Journal Volume: 62; Journal Issue: 8; Journal ID: ISSN 1613-4125
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; computational modeling; EGCG; gallic acid; GPCR; GPRC6A

Citation Formats

Pi, Min, Kapoor, Karan, Ye, Ruisong, Smith, Jeremy C., Baudry, Jerome, and Quarles, Leigh D. GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. United States: N. p., 2018. Web. doi:10.1002/mnfr.201700770.
Pi, Min, Kapoor, Karan, Ye, Ruisong, Smith, Jeremy C., Baudry, Jerome, & Quarles, Leigh D. GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. United States. doi:10.1002/mnfr.201700770.
Pi, Min, Kapoor, Karan, Ye, Ruisong, Smith, Jeremy C., Baudry, Jerome, and Quarles, Leigh D. Wed . "GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea". United States. doi:10.1002/mnfr.201700770. https://www.osti.gov/servlets/purl/1459287.
@article{osti_1459287,
title = {GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea},
author = {Pi, Min and Kapoor, Karan and Ye, Ruisong and Smith, Jeremy C. and Baudry, Jerome and Quarles, Leigh D.},
abstractNote = {1 Scope: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood.2 Methods and results: We found that GPRC6A, a multi-ligand-sensing G-protein-coupled receptor that regulates energy metabolism, sex hormone production, and prostate cancer progression, is a target for gallates. Sodium gallate (SG), gallic acid (GA) > ethyl gallate (EG) > octyl gallate (OG) dose dependently activated ERK in HEK-293 cells transfected with GPRC6A but not in non-transfected controls. SG also stimulated insulin secretion in β-cells isolated from wild-type mice similar to the endogenous GPRC6A ligands, osteocalcin (Ocn) and testosterone (T). Side-chain additions to create OG resulted in loss of GPRC6A agonist activity. Another component of green tea, epigallocatechin 3-gallate (EGCG), dose-dependently inhibited Ocn activation of GPRC6A in HEK-293 cells transfected with GPRC6A and blocked the effect of Ocn in stimulating glucose production in CH10T1/2 cells. Using structural models of the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A, calculations suggest that l-amino acids and GA bind to the VFT, whereas EGCG is calculated to bind to sites in both the VFT and 7-TM.3 In conclusion, GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effect of green tea consumption.},
doi = {10.1002/mnfr.201700770},
journal = {Molecular Nutrition & Food Research},
issn = {1613-4125},
number = 8,
volume = 62,
place = {United States},
year = {2018},
month = {2}
}

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