Ligand bias at metabotropic glutamate 1a receptors: molecular determinants that distinguish β-arrestin-mediated from G protein-mediated signaling.

Molecular Pharmacology
Andrew C EmeryJarda T Wroblewski

Abstract

The metabotropic glutamate 1a (mGlu1a) receptor is a G protein-coupled receptor linked with phosphoinositide (PI) hydrolysis and with β-arrestin-1-mediated sustained extracellular signal-regulated kinase (ERK) phosphorylation and cytoprotective signaling. Previously, we reported the existence of ligand bias at this receptor, inasmuch as glutamate induced both effects, whereas quisqualate induced only PI hydrolysis. In the current study, we showed that mGlu1 receptor agonists such as glutamate, aspartate, and l-cysteate were unbiased and activated both signaling pathways, whereas quisqualate and (S)-3,5-dihydroxyphenylglycine stimulated only PI hydrolysis. Competitive antagonists inhibited only PI hydrolysis and not the β-arrestin-dependent pathway, whereas a noncompetitive mGlu1 receptor antagonist blocked both pathways. Mutational analysis of the ligand binding domain of the mGlu1a receptor revealed that Thr188 residues were essential for PI hydrolysis but not for protective signaling, whereas Arg323 and Lys409 residues were required for β-arrestin-1-mediated sustained ERK phosphorylation and cytoprotective signaling but not for PI hydrolysis. Therefore, the mechanism of ligand bias appears to involve different modes of agonis...Continue Reading

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Citations

Jul 16, 2013·Trends in Pharmacological Sciences·Rita J ValentinoDebra Bangasser
Apr 2, 2013·Proceedings of the National Academy of Sciences of the United States of America·Marie-Laure Rives, Jonathan A Javitch
Feb 24, 2015·Neuropharmacology·Hannah A HathawayJarda T Wroblewski
May 27, 2014·Frontiers in Endocrinology·Peishen ZhaoNigel W Bunnett
Nov 26, 2016·Nature Communications·Andrew G EngGeoffrey T Swanson
Mar 23, 2017·Journal of Cardiovascular Pharmacology·Pierre-Yves Jean-CharlesSudha K Shenoy
Nov 6, 2018·Clinical Science·Phuc N H TrinhKaren J Gregory
Jul 29, 2018·The Journal of Pharmacology and Experimental Therapeutics·Carrie Bowman DalleyJarda T Wroblewski
Oct 19, 2014·Molecular Pharmacology·Yuh-Jiin I JongKaren L O'Malley
Mar 27, 2015·Molecular Pharmacology·Karen J Gregory, P Jeffrey Conn
Jul 21, 2020·ChemMedChem·Zoltán OrgovánGyörgy M Keserű
Aug 25, 2017·Biophysics Reviews·Ana Maria Bernal CorreaChristopher Kushmerick
Jul 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Linn Samira Mari EvensethIngebrigt Sylte
Jan 16, 2016·Addiction Biology·Bailey W MillerKaren K Szumlinski

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