Molecular basis for the differential agonist affinities of group III metabotropic glutamate receptors

Molecular Pharmacology
Erica RosemondD R Hampson

Abstract

Agonist stimulation of group III metabotropic glutamate receptors (mGluRs) induces an inhibition of neurotransmitter release from neurons. The group III mGluRs are pharmacologically defined by activation with the glutamate analog L-amino-4-phosphonobutyric acid (L-AP4). The affinities of these receptors for L-AP4 and glutamate vary over approximately a 1500-fold concentration range. The goal of this study was to elucidate the molecular basis for this dispersion of agonist affinities for the group III receptors mGluR4, mGluR6, and mGluR7. [3H]L-AP4 binding was present in human embryonic kidney cells transfected with the high-affinity mGluR4 receptor but not in cells transfected with mGluR6 or the low-affinity mGluR7 receptor. Analysis of mGluR4/mGluR6 receptor chimeras revealed that replacement of the first 35 amino acids of mGluR6 with the first 50 amino acids of mGluR4 was sufficient to impart [3H]L-AP4 binding to mGluR6. Homology models of mGluR4 and mGluR7 were used to predict amino acids that may affect ligand affinity. Mutations were made in mGluR7 to convert selected residues into the equivalent amino acids present in the high-affinity mGluR4 receptor. The mGluR7 N74K mutation caused a 12-fold increase in affinity in a fu...Continue Reading

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Citations

Apr 14, 2007·Visual Neuroscience·Lawrence H PintoJoseph S Takahashi
Sep 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Donghui KuangBelinda S W Chang
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Takanori MutoHisato Jingami
Dec 24, 2013·Pharmacology & Therapeutics·Lucyna Pomierny-ChamiołoMałgorzata Filip
Apr 9, 2005·Journal of Neurochemistry·Donghui KuangDavid R Hampson
Mar 21, 2009·British Journal of Pharmacology·P Wellendorph, H Bräuner-Osborne
Oct 11, 2012·The Journal of Comparative Neurology·Marion F HaugStephan C F Neuhauss
Nov 22, 2005·Bioorganic & Medicinal Chemistry·Minghua Wang, David R Hampson
Jan 10, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cyril GoudetJean-Philippe Pin
Oct 2, 2019·Current Neuropharmacology·E PalazzoS Maione
Apr 12, 2017·Proceedings of the National Academy of Sciences of the United States of America·Joshua LevitzEhud Y Isacoff
Feb 4, 2006·The Journal of Biological Chemistry·Minghua WangDavid R Hampson

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