G-protein-coupled receptors are well known for converting an extracellular signal into an intracellular response. Here we showed that the metabotropic glutamate receptor 5 (mGlu5) plays a dynamic intracellular role in signal transduction. Activation of endogenously expressed mGlu5 on striatal nuclear membranes leads to rapid, sustained calcium (Ca2+) responses within the nucleoplasm that can be blocked by receptor-specific antagonists. Extracellular ligands such as glutamate and quisqualate reach nuclear receptors via both sodium-dependent transporters and cystine glutamate exchangers. Inhibition of either transport system blocks radiolabeled agonist uptake as well as agonist-induced nuclear Ca2+ changes. Impermeable antagonists like LY393053 and LY367366 not only blocked [3H]quisqualate binding but also prevented nontransported agonists such as (RS)-3,5-dihydroxyphenylglycine from inducing intracellular Ca2+ changes in heterologous cells. In contrast, neither LY compound prevented quisqualate or glutamate from activating intracellular receptors leading to Ca2+ responses. Inasmuch as Ca2+ can enter the nucleoplasm via the nuclear pore complex or from the nuclear lumen, the presence of nuclear mGlu5 receptors appeared to amplify the latter process generating a faster nuclear response in heterologous cells. In isolated striatal nuclei, nuclear receptor activation results in the de novo appearance of phosphorylated CREB protein. Thus, activation of nuclear mGlu5 receptors initiates a signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. These studies demonstrated that mGlu5 receptors play a dynamic role in signaling both on and off the plasma membrane.

01 Sep 2002·Neuroscience LettersQ4 · MEDICINE

Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists

Q4 · MEDICINE

Article

Author: Gerald Kelly ; Barry P. Clark ; Michael P. Johnson ; Darryle D. Schoepp ; Ann E. Kingston ; Mary Jo Chamberlain ; Richard S. Baker ; Kelly Griffey ; Rebecca A. Wright ; Joseph P. Tizzano ; Rosemarie Tomlinson ; John R. Harris ; Bryan G. Johnson

A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol). Further antagonist actions were also demonstrated in a model of (RS)-DHPG-induced PI hydrolysis in vivo such that LY367385 and the active cis isomer of LY393053 produced dose-dependent inhibition of PI responses in both cerebellum and hippocampus. Cis LY393053 also inhibited hippocampal PI responses when administered intraperitoneally at a dose of 30 mg/kg. These compounds define a new series of group I mGlu receptor antagonists which may serve as useful experimental tools.

01 Jan 2002·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Group I Metabotropic Glutamate Receptor Antagonists Block Secondary Thermal Hyperalgesia in Rats with Knee Joint Inflammation

Q3 · MEDICINE

Article

Author: Lu, Ying ; Westlund, Karin N. ; Chen, Ying ; Zhang, Liping

Activation of ionotropic glutamate receptors has been shown previously to be essential for the development of secondary thermal hyperalgesia. The present study assessed involvement of group I metabotropic glutamate receptors (mGlu) in both the induction and maintenance phases of secondary thermal hyperalgesia initiated by knee joint inflammation in rats. The dose dependence of each drug in antagonism of thermal hypersensitivity was demonstrated in pre- and post-treatment paradigms. Knee joint inflammation was induced by injection of kaolin and carrageenan. Four hours later the paw withdrawal latencies were significantly shorter than baseline values. Rats were pretreated by spinal microdialysis infusion of group I mGlu receptor antagonists, LY393053 [(+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid], LY367385 [(S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid], or AIDA [(R,S)-1-aminoindan-1,5-dicarboxylic acid/UPF 523] before knee joint injection. The paw withdrawal latencies measured 4 h after the injection were significantly longer in the presence of group I mGlu receptor antagonists than those of the artificial cerebrospinal fluid-treated arthritic control group. Post-treatment with the group I mGlu receptor antagonists LY367385 and AIDA allowed significant recovery of the paw withdrawal latencies after the onset of the knee joint inflammation. The knee joint inflammation itself was not affected by either treatment. The results of the present study indicate that secondary thermal hyperalgesia can be effectively attenuated during both the development and maintenance phases of acute knee joint inflammation by spinal application of specific group I mGlu receptor antagonists.

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Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Diseases	Discovery	US	Eli Lilly & Co.	20 Sep 2002

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