Transposition of three amino acids transforms the human metabotropic glutamate receptor (mGluR)-3-positive allosteric modulation site to mGluR2, and additional characterization of the mGluR2-positive allosteric modulation site

The Journal of Pharmacology and Experimental Therapeutics
Blake RoweLorrie P Daggett

Abstract

Glutamate is a major neurotransmitter in the central nervous system, and abnormal glutamate neurotransmission has been implicated in many neurological disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy, and pain. Metabotropic glutamate receptors (mGluRs) activate intracellular signaling cascades in a G protein-dependent manner, which offer the opportunity for developing drugs that regulate glutamate neurotransmission in a functionally selective manner. In the present study, we further characterize the human mGluR2 (hmGluR2) potentiator binding site by showing that the substitution of the three amino acids found to be required for hmGluR2 potentiation, specifically Ser(688), Gly(689), and Asn(735), with the homologous hmGluR3 amino acids, inactivates the positive allosteric modulator activity of several structurally unique mGluR2 potentiators. Based on the characterization of the hmGluR2 potentiator binding site, we developed a novel scintillation proximity assay that was able to discriminate between compounds that were hmGluR2-specific potentiators, and those that were active on both hmGluR2 and hmGluR3. In addition, we substituted Ser(688), Gly(689), and Asn(7...Continue Reading

References

May 1, 1994·Neurochemistry International·D D Schoepp
Jan 1, 1997·Annual Review of Pharmacology and Toxicology·P J Conn, J P Pin
Aug 12, 1999·European Journal of Pharmacology·J P PinF Acher
May 3, 2001·Nature·J Ziauddin, D M Sabatini
Oct 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·F KnoflachJ A Kemp
Jun 27, 2002·Trends in Pharmacological Sciences·Marie-Laure ParmentierJean-Philippe Pin
May 29, 2003·Current Drug Targets. CNS and Neurological Disorders·Laura E Chavez-NoriegaUna C Campbell
May 29, 2003·Current Drug Targets. CNS and Neurological Disorders·M A Varney, R W Gereau
Jun 26, 2003·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Daniel S LorrainLinda J Bristow
Oct 16, 2003·Current Opinion in Pharmacology·Lauren T May, Arthur Christopoulos
Sep 24, 2004·Bioorganic & Medicinal Chemistry Letters·Essa HuNicholas D P Cosford
Jul 26, 2005·Bioorganic & Medicinal Chemistry Letters·Theodore M KameneckaJeffery J Anderson
Jul 28, 2005·Bioorganic & Medicinal Chemistry Letters·Céline BonnefousTheodore M Kamenecka
Jul 5, 2006·Science's STKE : Signal Transduction Knowledge Environment·Terry Kenakin
Apr 10, 2007·The Journal of Pharmacology and Experimental Therapeutics·Kamondanai HemstapatP Jeffrey Conn
Jul 17, 2007·Trends in Pharmacological Sciences·Thue W Schwartz, Birgitte Holst
Jul 17, 2007·Trends in Pharmacological Sciences·Katie LeachArthur Christopoulos
Jul 24, 2007·Trends in Pharmacological Sciences·Annette Gilchrist

❮ Previous
Next ❯

Citations

Jan 31, 2012·Acta Pharmacologica Sinica·Lei ChunJian-feng Liu
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·Colleen M Niswender, P Jeffrey Conn
Nov 22, 2015·British Journal of Pharmacology·Maarten L J DoornbosLaura H Heitman
Dec 9, 2008·Trends in Pharmacological Sciences·P Jeffrey ConnCarrie K Jones
Jul 8, 2015·Trends in Neurosciences·Amr EllaithyDiomedes E Logothetis
May 31, 2011·Neuropharmacology·Paige N Vinson, P Jeffrey Conn
Jun 27, 2017·Structure·Laura Pérez-BenitoGary Tresadern
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Mar 17, 2018·Molecular Pharmacology·Daniel E O'BrienP Jeffrey Conn
Mar 27, 2015·Molecular Pharmacology·Karen J Gregory, P Jeffrey Conn
Jul 21, 2020·ChemMedChem·Zoltán OrgovánGyörgy M Keserű
Jun 27, 2019·Expert Opinion on Therapeutic Patents·Andrés A TrabancoJosé María Cid

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.