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

Min Pi, Karan Kapoor, Ruisong Ye, Jeremy C. Smith, Jerome Baudry, Leigh Quarles

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Scope: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood. 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. Conclusion: GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effect of green tea consumption.

Original languageEnglish (US)
Article number1700770
JournalMolecular Nutrition and Food Research
Volume62
Issue number8
DOIs
StatePublished - Apr 1 2018

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Venus
Gallic Acid
Dionaea muscipula
epigallocatechin
Osteocalcin
green tea
Tea
Biological Products
Diptera
osteocalcin
HEK293 Cells
gallic acid
Sodium
agonists
Ligands
Structural Models
sodium
Gonadal Steroid Hormones
cells
G-Protein-Coupled Receptors

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Food Science

Cite this

GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. / Pi, Min; Kapoor, Karan; Ye, Ruisong; Smith, Jeremy C.; Baudry, Jerome; Quarles, Leigh.

In: Molecular Nutrition and Food Research, Vol. 62, No. 8, 1700770, 01.04.2018.

Research output: Contribution to journalArticle

Pi, Min ; Kapoor, Karan ; Ye, Ruisong ; Smith, Jeremy C. ; Baudry, Jerome ; Quarles, Leigh. / GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. In: Molecular Nutrition and Food Research. 2018 ; Vol. 62, No. 8.
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abstract = "Scope: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood. 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. Conclusion: GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effect of green tea consumption.",
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