The Interaction Between CAL and mGluR1 Alleviates Cytotoxicity Induced by mGluR1 Overactivation / 中国生物化学与分子生物学报

Glutamate excitotoxicity mediated by metabotropic glutamate receptor 1 (mGluR1) overexpression or overactivation plays an important role in the development of Parkinson's disease (PD). Although clinical trials support the therapeutic potential of certain mGluR negative allosteric modulators (NAMs), there are still some limitations of precise modulation of mGluR using NAMs. Thus, the identification of small molecules or endogenous genes that facilitate mGluR1 modulation might be potentially beneficial for PD treatment. We determined the role of interacting partner cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) in overactivated mGluR1-mediated cell apoptosis and signaling pathway in vitro and in vivo. HEK293 cells were used as an experimental tool to directly examine the interaction between CAL and mGluR1. We found that agonist of mGluR1 significantly enhanced the interaction between CAL and mGluR1 (P< 0. 05). Furthermore, CAL suppressed overactivated mGluR1-induced cell apoptosis and the activation of mGluR1 downstream signaling pathways. CAL overexpression relieved rotenone-induced neuron death (P< 0. 001) by inhibiting the activation of mGluR1-mediated signaling pathways in rotenone-induced rat model of PD. This study may reveal a new mechanism of mGluR1 activity regulation, and hopefully provide a novel molecular mechanism for the nervous system related diseases.

Association between Metabotropic Glutamate Receptor 1 Polymorphism and Cardiovascular Disease in Korean Adults

OBJECTIVE: The mGluR1 (metabotropic glutamate receptor 1) gene, a G protein–coupled receptor, is known to mediate perceptions of umami tastes. Genetic variation in taste receptors may influence dietary intake, and in turn have an impact on nutritional status and risk of chronic disease. We investigated the association of mGluR1 rs2814863 polymorphism with lipid profiles and cardiovascular disease (CVD) risk, together with their modulation by macronutrient intake in Korean adults. METHODS: The subjects consisted of 8,380 Koreans aged 40-69 years participating in the Anseong and Ansan Cohort Study, which was a part of the Korean Genome Epidemiology Study (KoGES). Data was collected using self-administered questionnaires, anthropometric measurements, and blood chemical analysis. RESULTS: Carriers of C allele at mGluR1 rs2814863 was associated with decreased high density lipoprotein cholesterol (HDL-C) and increased triglyceride as compared to carriers of TT. Also, carriers of the C allele showed higher fat intake and lower carbohydrate intake than those with carriers of TT. After adjustment for multiple testing using false-discovery rate method, the significant difference of HDL-C, triglyceride, dietary fat, and carbohydrate across genotypes disappeared. Gene-diet interaction effects between rs2814863 and macronutrients intake were not significantly associated with HDL-C and triglyceride levels. However, carriers of C allele demonstrated significantly higher odds of CVD {odds ratio=1.13, 95% CI=1.02-1.25} compared with carriers of TT. CONCLUSIONS: Our findings support significant associations between the mGluR1 rs2814863 genotype and CVD-related variables in Korean adults. However, these associations are not modified by macronutrient intake.

Role of protein tyrosine phosphatase SHP-2 in group I metabotropic glutamate receptors-induced allodynia / 中国药理学通报

Aim To investigate whether the pain modi-fication by group I metabotropic glutamate receptors (mGluRs)required the involvement of Src homology-2 domain-containing phosphatase-2 (SHP-2 ).Methods Co-immunoprecipitation was performed to examine the possible interaction between SHP-2 and group I mGluRs in spinal cord dorsal horn of mice.By measur-ing the paw withdrawal thresholds,the effects of SHP-2 inhibitor NSC-87877 or its catalytically inactive SHP-2 (C459S ) mutant on allodynia induced by group I mGluRs agonist DHPG (50 nmol)were observed.Re-sults Anti-mGluR5 antibody was able to co-immuno-precipitate SHP-2 from spinal dorsal horn of mice, while no SHP-2 was precipitated by anti-mGluR1 anti-body.Inactivation of SHP-2 by NSC-87877 (6 nmol) or SHP-2 (C459S ) effectively attenuated allodynia caused by DHPG.Conclusion SHP-2 can physically interact with mGluR5.The activation of SHP-2 may be necessary for group I mGluRs to process the nocicep-tive information.

Regulation of DREAM Expression by Group I mGluR

DREAM (downstream regulatory element antagonistic modulator) is a calcium-binding protein that regulates dynorphin expression, promotes potassium channel surface expression, and enhances presenilin processing in an expression level-dependent manner. However, no molecular mechanism has yet explained how protein levels of DREAM are regulated. Here we identified group I mGluR (mGluR1/5) as a positive regulator of DREAM protein expression. Overexpression of mGluR1/5 increased the cellular level of DREAM. Up-regulation of DREAM resulted in increased DREAM protein in both the nucleus and cytoplasm, where the protein acts as a transcriptional repressor and a modulator of its interacting proteins, respectively. DHPG (3,5-dihydroxyphenylglycine), a group I mGluR agonist, also up-regulated DREAM expression in cortical neurons. These results suggest that group I mGluR is the first identified receptor that may regulate DREAM activity in neurons.

The protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate or oxygen-glucose deprivation / 中国康复理论与实践

@#ObjectiveTo investigate the protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate (Glu) or oxygen-glucose deprivation (OGD).MethodsNeuron damage induced by Glu or OGD, as well as the action of (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) were measured by determining the leakage of lactate dehydrogenase (LDH) from neurons. Immunocytochemistry and immunofluorescent methods were used to detect the expression of anti-mGluR1α. Morphological observation of primary cortical neurons was performed by phase contrast microscope.ResultsFollowing the exposure to 0.1 mmol/L Glu for 1 h or OGD for 1 h, LDH leakage from neurons obviously increased (P< 0.01 ). 50 mmol/L LY367385, when co-incubated with Glu or OGD, markedly reduced the LDH leakage (P<0.01). The 24-h leakage of LDH was increased from cells exposed to 0.1 mmol/L Glu for 15 min. Pre-and post-treatment with LY367385 (50 mmol/L ) decreased the leakage of LDH. The cultured neurons expressed mGluR1α.ConclusionLY367385 has protective effect on neurons damaged by Glu or OGD. It may be related to antagonizing mGluR1α.

The effects of a rotating magnetic field on Li pilocarpine-induced seizures in rats / 中华物理医学与康复杂志

Objective To study the effects of a rotating magnetic field(RMF)on Li pilocarpine-in- duced seizure activity and the expression of mGluR1 and mGluR5 in the hippocampus.Methods Thirty rats were divided into 5 groups.Each rat in the model(M),short treatment(ST)and long treatment(LT)groups was treated with intra-peritoneal injections of lithium chloride(60 mg/kg),followed by an intra-peritoneal injec- tion of pilocarpine(35 mg/kg)24 h later.The rats in the ST group were exposed to 20 mT RMF for 20 min ev- ery day for 3 d before seizure induction,while the rats in LT group were exposed to the same RMF for 8 d.The latency,severity and duration of seizure,as well as accompanying symptoms and electroencephalogram data, were recorded,and the expression of mGluR1 and mGluR5 was calculated using an electrophoretic imaging anal- ysis system.Results The duration,times and accompanying symptoms of seizure were significantly decreased in the LT group.The mGluR1 mRNA level and mGluR1/mGluR5 ratio in the M group were markedly increased, but the mGluR5 mRNA level was obviously decreased,while the expression of mGluR1 in the ST and LT groups was decreased,and mGluR5 was increased.Conclusions Seizure activity in rats can be inhibited by 20 mT RMF,and the expression of mGluRl and mGluR5 in the hippocampus of rats suffering seizures can be markedly influenced by longer-term RMF.

Expression of mGluR1 in hippocampus of spontaneously epileptic rats / 中国药理学通报

Aim To investigate the expression of mGluR1 in hippocampus of spontaneously epileptic rats(SER) by control study.Methods Total RNA was extracted from hippocampus of SER and Wistar rats,and mGluR1 mRNA expression was detected by RT-PCR;the expression of mGluR1 protein was detected by immunohistochemistry and Western blot.Results mGluR1 mRNA of SER was lower than that of Wistar rats in hippocampus(P0.05) were found.In positive cells,mGluR1 proteins were enhanced.By Western blot,total mGluR1 protein was down-regulated in SER hippocampus(P

THE CHANGE IN mGluR1? IN CA_1 AFTER INFRASONIC DAMAGE AND THE EFFECT OF ITS ANTAGONIST MCPG / 解放军医学杂志

To study the change in mGluR1? in CA 1 after infrasonic damage and the effect of its antagonist MCPG,120 SD rats were randomizied into infrasonic damage group and MCPG therapy group.The two groups were subdivided into control group and 1 challenge, 7 chellenges, 14 challenge groups respectively,each group consisted of 15 rats. Rats were exposed to 8Hz 130dB infrasound as designed,2h for each challenge.The mGluR1? was stained by immunohistochemistry method.The changes in mGluR1? and cell pattern were observed under light and electronic microscopes.The results showed the number of mGluR1? positive neurons increased after 1 challenge infrasonic damage( P 0 05).MCPG had an effect to protect neuron from infrasonic damage as identified by morphology.It is concluded that the change of mGluR1? activity could mediate excitotoxicity and was one of the major factors related with neuron injury after infrasound.