Research progress of metabotropic glutamate receptor 5 in related central nervous system diseases / 中国药科大学学报

@#As a key component of glutamatergic system, metabotropic glutamate receptor 5 (mGluR5) has been extensively involved in the regulation of physiological processes such as synaptic transmission, synaptic plasticity and synaptic excitation/inhibition balance.Over the past few decades, mGluR5 has been found to be closely related to multiple neurological and psychiatric disorders, thus it is of considerable interest as a drug target in the treatment of such disorders.This review summarizes the structure and distribution of mGluR5, its normal physiological function, its pathological roles in related central nervous system (CNS) diseases, as well as the current status of its drug development, in order to provide reference for further investigation.

Regulatory effect of metabolic glutamate receptor 1 on maltolate aluminum-induced synaptic plasticity in rats / 中国职业医学

OBJECTIVE: To observe the effect of maltolate aluminum on synaptic plasticity in the hippocampus of rats and to explore the regulatory effect and mechanism of metabotropic glutamate receptor 1(mGluR1). METHODS: Specific pathogen free healthy adult male SD rats were randomly divided into control group, aluminum group, aluminum agonist group and aluminum antagonist group, 8 rats in each group. The rats in the control group received no treatment; the rats in aluminum group were injected with 5 μL 10 mmol/L maltolate aluminum solution into the lateral ventricle; the rats in aluminum agonists and aluminum antagonist group were injected with 3 μL 10 mmol/L maltolate aluminum solution plus 2 μL 0.1 μmol/L mGluR1 agonist or 2 μL 0.2 μmol/L mGluR1 antagonists into the lateral ventricle, respectively.Maltolate aluminum solution was injected every 2 days and continued for 10 days. After maltolate aluminum exposure, the amplitudes of long-term potentiation(LTP) in hippocampal CA1 region of rats were measured, and the relative expression levels of mRNA and protein of mGluR1, N-methyl-D-aspartate receptor(NMDAR1) and protein kinase C(PKC) in hippocampus tissue of rats were detected by real-time fluorescence quantitative polymerase chain reaction and Western blotting. RESULTS: The amplitude of LTP in hippocampal CA1 region in aluminum group and aluminum agonist group was lower than that in the control group and the aluminum antagonist group(P<0.05). Compared with the control group, the relative expression of mGluR1 mRNA and protein in the aluminum group increased, the relative expression of PKC and NMDAR1 mRNA and protein in the aluminum group decreased(P<0.05). Compared with the aluminum group, the relative expression of mGluR1 mRNA and protein in the aluminum agonist group increased, while the NMDAR1 mRNA decreased(P<0.05); the relative expression of mGluR1 mRNA and protein in the aluminum antagonist group decreased, while the NMDAR1 mRNA and protein increased(P<0.05). Compared with the aluminum agonist group, the relative expression of mGluR1 mRNA and protein decreased, while the NMDAR1 mRNA and protein increased in the aluminum antagonist group(P<0.05). The relative expression level of PKC mRNA and protein in aluminum agonist group and aluminum antagonist group was not statistically significant(P>0.05), and there was no statistical significance in these two groups compared with control group and aluminum group(P>0.05). CONCLUSION: Maltolate aluminum exposure can inhibit synaptic plasticity by inhibiting LTP in hippocampus of rats, and the mechanism may be related to the regulation of NMDAR1 expression by mGluR1.

Critical role of metabotropic glutamate receptor 4 in bone marrow-derived dendritic cells in the Th17 cell differentiation and the melanogenesis of B16 cells

Vitiligo is an acquired pigmentary disorder resulting from selective destruction of melanocytes. Emerging studies have suggested that T helper cell 17 (Th17) is potentially implicated in vitiligo development and progression. It was recently discovered that metabotropic glutamate receptor 4 (mGluR4) can modulate Th17-mediated adaptive immunity. However, the influence of mGluR4 on melanogenesis of melanocytes has yet to be elucidated. In the present study, we primarily cultured mouse bone marrow-derived dendritic cells (BMDC) and then knocked down and over-expressed mGluR4 using transfection. Transduced BMDC were co-cultured with CD4+ T cells and the expression of Th17-related cytokines were measured. The morphology and melanogenesis of B16 cells were observed after being treated with co-culture medium of CD4+ T cells and transduced BMDC. We found that mGluR4 knockdown did not affect the co-stimulatory CD80 and CD86 upregulation after lipopolysaccharide stimulation but did increase the expression of Th17-related cytokines, and further down-regulated the expression of microphthalmia-associated transcription factor (MITF) and the downstream genes, decreased melanin production, and destroyed the morphology of B16 cells. Conversely, over-expression of mGluR4 reduced the expression of CD80 and CD86, suppressed the production of Th17-related cytokines, increased the expression of MITF, and did not destroy the morphology of B16 cells. Our study confirmed that mGluR4 modulated the Th17 cell polarization and resulted in the alteration of melanogenesis and morphology of B16 cells. Collectively, these findings suggest mGluR4 might be a potent target involved in the immune pathogenesis of vitiligo.

Research progress in metabotropic glutamate receptor 5 and related nervous system diseases / 中国药理学与毒理学杂志

The metabotropic glutamate receptor 5 (mGluR5), one of the most important mGluRs, exerts a biological effect through the second messenger. mGluR5 is mainly distributed in the cerebral cortex, hippocampus, and striatum in the form of dimers. It participates in neuronal excitability network regulation, neurogenesis, and synaptic plasticity associated with learning and memory by activating signaling pathways such as protein kinase C-inositol 1, 4, 5-triphosphate-diacylglycerol-Ca2+ and phosphatidylinositol 3-kinase-mammalian target of Rapamycin. Recently, mGluR5 has been confirmed to play an important role in diseases of the nervous system. Studies have shown that over-activation or inhibition of mGluR5 is closely related to the pathological processes of a variety of neurological diseases. A variety of drugs that selectively activate or inhibit mGluR5 activity have been used in the treatment of neurological diseases.

Role of group mGluR in low dose ketamine protecting learning and memory function after electroconvulsive shock in depression rats / 上海交通大学学报（医学版）

Objective • To investigate the role of group I metabotropic glutamate receptor (mGluR) in the regulation of N-methyl-D-aspartic acid receptor (NMDAR)-mediated synaptic plasticity in low dose ketamine protecting learning and memory function after modified electroconvulsive shock (MECS). Methods • The 2-3-month-old Sprague Dawley (SD) rats were used to establish depression models with chronic unpredictable mild stress. Ten healthy rats were used as the control group (group C), and another 30 depressed rats were randomly divided into group D, group M, and group KM. Group C was not treated, group D was treated with pseudo-MECS after intraperitoneal injection of normal saline, group M was given intraperitoneal injection of propofol, and group KM was given intraperitoneal injection of propofol combined with low-dose ketamine (10 mg/kg). Both group M and group KM underwent MECS. The sucrose preference test was used to evaluate the depression status. The Morris water maze was used to detect the spatial learning and memory function. The expression of NMDAR1, mGluR1 and mGluR5 proteins in the hippocampus was detected by Western blotting. Another 36 depressed rats were randomly divided into 6 groups: group DE, group m1E, group m5E, group DE', group m1E', and group m5E'. Group DE and group DE' were perfused with artificial cerebrospinal fluid alone. Group m1E and group m1E' were perfused with artificial cerebrospinal fluid containing mGluR1 blocker. Group m5E and group m5E' were perfused with artificial cerebrospinal fluid containing mGluR5 blocker. Long-term potentiations (LTP) were detected in group DE, group m1E, and group m5E. NMDAR-mediated field potentials (fEPSPNMDAR) were detected in group DE', group m1E', and group m5E'. Results • After treatment, the sucrose preference percentages of group M and group KM increased compared with group D (P<0.05), the escape latencies (EL) of group M and group KM were prolonged (P<0.05), and the space exploration times (SET) were shortened (P<0.05). Compared with group M, the EL of group KM was shortened (P<0.05), and the SET was prolonged (P<0.05). Compared with group D, the expression levels of NMDAR1, mGluR1 and mGluR5 in group M and group KM decreased (P<0.05). Compared with group M, the expression levels of NMDAR1, mGluR1 and mGluR5 in group KM increased (P<0.05). Compared with group DE, the LTP decreased in group m1E and group m5E (P<0.05). Compared with group DE', the fEPSPNMDAR of group m1E' and group m5E' decreased (P<0.05). Conclusion • Ketamine up-regulates NMDAR1 and group mGluR expression to enhance the activation of NMDAR in the hippocampus which may be responsible for the protective effects on spatial learning and memory function in depression rats undergoing MECS.

Protective effect of metabotropic glutamate receptor 1 negative allosteric modulator JNJ16259685 on neuron after subarachnoid hemorrhage in rats / 中国脑血管病杂志

Objective To investigate the protective effect and its mechanism of metabotropic glutamate receptor 1 ( mGluR1) negative allosteric modulator JNJ16259685 on neuron after subarachnoid hemorrhage (SAH) in rats. Methods Ninety SPF-grade SD male rats were selected. They were randomly divided into 3 groups:sham operation group (n=18),SAH+placebo group (n=36),and SAH+JNJ16259685(JNJ) group (n=36). A SAH model was induced by intravascular puncture. SAH +placebo group received intraperitoneal injection of aseptic water containing 5% dimethyl sulfoxide (DMSO) at 2,24 and 48 h after operation. The SAH+JNJ group was intraperitoneally injected with 1 mg/kg JNJ16259685 ( dissolved in sterile water in 5% DMSO). Garcia scoring criteria were used to assess neurological deficits at 72 h after SAH. Dry and wet weight method was used to detect brain edema. Evans Blue method was used to assess blood-brain barrier permeability. A calcium assay kit was used to detect the mitochondrial calcium ion concentration. Immunofluorescence staining was used to observe neuronal apoptosis. GraphPad 7. 0 software was used to conduct one-way analysis of variance in all indicators among the 3 groups. Results Compared with the sham operation group,the Garcia score (11. 0 ± 0. 4) decreased in the SAH+placebo group. The water content in left and right hemispheres was 80. 5 ± 0. 1% and 80. 3 ± 0. 2% respectively,the Evans blue dye extravasation (2. 8 ± 0. 2),basal cortical mitochondrial calcium ion concentration (2. 5 ± 0. 3),and neuronal apoptosis in basal cortex and hippocampus CA1 region (the number of active caspase-3/NeuN positive cells was 300 ±30/mm2and 20 ± 2/mm respectively) increased (all P<0. 05);and the Garcia score (13. 0 ± 0. 5) was significantly higher in the SAH+JNJ group than in the SAH+placebo group. Water content in left and right hemispheres was 79. 8 ± 0. 2% and 79. 3 ± 0. 1% respectively,Evans blue dye extravasation (1. 8 ±0. 2),basal cortex mitochondrial calcium ion concentration (1. 7 ± 0. 1),basal cortex and the number of neuronal apoptosis in hippocampal CA1 region (the number of active caspase-3/NeuN positive cells were 180 ± 10/mm2,12 ±2/mm) reduced compared with the SAH+placebo group (all P<0. 05). Conclusion After SAH,JNJ16259685 relieves cerebral edema and reduces blood-brain barrier permeability,inhibits the increase of cortical mitochondrial calcium ion concentration,and reduces neuronal apoptosis,thereby exerting neuroprotective effects.

Effect of Serum on Cultured Astrocytes Morphology and Expression of Aquaporin-4 in Rats / 中国康复理论与实践

Objective To explore the effect of blood-brain barrier disruption on expression of AQP-4,through comparing the cell morphology and the expression of aquaporin-4(AQP-4)of cultured astrocytes in medium with and without fetal bovine serum(FBS). Methods Cerebral cortical astrocytes from female Wistar rats were cultured in serum free medium,DMEM supplement-ed with 10% FBS,and serum free medium supplemented with 10% FBS.Phase contrast microscope was used to detect the cell morphology and cell size. Immunofluorescence staining and reverse real-time quantitative poly-merase chain reaction(RT-qPCR)were used to examine the expression of glial fibrillary acidic protein(GFAP), AQP-4 and metabotropic glutamate receptor 5(mGluR5). Results Astrocytes in serum free medium showed extensive process bearing morphology,small body and nucleus,and high refractivity.In contrast,in two kinds of 10% FBS-containing medium,astrocytes were flat with large body and nucleus,weak refractivity,as well as short process.Analysis of immunofluorescence staining and RT-qPCR revealed a down-regulation of GFAP and AQP-4 protein and mRNA expression in two kinds of 10% FBS-con-taining medium, compared with that in serum free medium (P<0.001), however, there was no difference in mGluR5 protein and mRNA expression(P>0.05). Conclusion FBS changed astrocyte morphology and down-regulated the expression of GFAP and AQP-4.

Relationship between metabotropic glutamate receptor 5 and N-methyl-D-aspartate receptor and their roles in diseases / 上海交通大学学报（医学版）

Metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor (NMDAR) belongs to metabotropic and ionotropic glutamate receptor family, respectively. In recent years, a lot of attention has been paid to these two types of glutamate receptors in the field of neuroscience and psychiatry. This article mainly summarized the research progress of the relationship between these two kinds of receptors and the influence of their relationship on different diseases.

Metabotropic glutamate receptor 5 and related clinical diseases / 基础医学与临床

mGlu5 (Metabotropic glutamate receptor 5) does not only exist in nervous system , but also in many pe-ripheric organs and tissues .The vital role that mGlu5 plays in both nervous and non-nervous system diseases , which will be important for further studying the pathogenesis of diseases .Moreover, it can provide us with new ide-as and methods for precaution and cure of illness with mGluRs .

Expression of Glu、mGluR 5 and EAAT 1 in bone tissues of ovariectomized osteoporotic rats and the effects of Total Flavonoids of Rhizoma Drynariae on it / 中国生化药物杂志

Objective To observe the expression of Glu、mGluR 5 and EAAT 1 in bone tissues of ovariectomized osteoporotic rats and the effects of Total Flavonoids of Rhizoma Drynariae (TFRD) on it. Methods 45 SPF 3-month-old Sprague-Dawley (SD) female rats were randomly divided into sham operation (Sham, n=15) group and ovariectomized (OVX, n=30) group. The osteoporotic(OP) model was established by bilateral ovariectomy, 14 weeks later, we measured bone mineral density(BMD) by dual-energy X-ray and determined that OP model was successfully replicated, OVX group rats were then divided into OVX group (n=15) and OVX+TFRD group (n=15). The OVX+TFRD group was given TFRD for 12 weeks. Glutamate (Glu), metabotropic glutamate receptor 5 (mGluR 5), and Glutamate/Aspartate Transporter (GLAST/EAAT 1)’s expression of femur was examined in order to clarify the characteristics of bone glutamate signaling pathway and the effects of TFRD on it. Results Glu and ionotropic receptors mGluR 5 mainly distributed in bone marrow cells and osteoblasts closed to the bone marrow cavity walls. There were no significant differences in Glu expression among Sham group, OVX group and OVX+TFRD group. The mGluR 5 expression of OVX+TFRD group was significantly higher than that of Sham group and OVX group(P=0.009), while no significant difference was found between the latter two groups. In addition to large distribution in bone marrow cells, small amount of transporter EAAT 1 was noted to express in bone cells of the bone lacunae. There were no significant differences in EAAT 1 expression among the three groups. Conclusion In bone glutamate signaling pathway, this study demonstrated that TFRD could significantly improve the ionotropic receptor mGluR 5’s expression, but had no inlfuence for Glu and EAAT 1.

Expression of Metabotropic Glutamate Receptors in the Medial Vestibular Nucleus Following Acute Hypotension in Rats / 대한평형의학회지

BACKGROUND AND OBJECTIVES: Acute hypotension induces expression of c-Fos protein and phosphorylated extracellular signal-regulated kinase (pERK), and glutamate release in the vestibular nuclei. Expression of c-Fos protein and pERK is mediated by the excitatory neurotransmitter, glutamate. In this study, the signaling pathway of glutamate in the vestibular nuclei following acute hypotension was investigated. MATERIALS AND METHODS: Expression of metabotropic glutamate receptors (mGluRs) was measured by Western blotting in the medial vestibular nucleus following acute hypotension in rats. RESULTS: Expression of pGluR1 Ser831, a subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, peaked at 30 minutes after acute hypotension insult, and expression of pNR2B, a subtype of N-methyl-D-aspartate (NMDA) receptors, peaked at 2 hours after acute hypotension insult. Acute hypotension induced expression of Homer1a and group I mGluR in the medial vestibular nucleus. Expression of mGluR1 and mGluR5 peaked at 6 hours following acute hypotension insults. CONCLUSION: These results suggest that afferent signals from the peripheral vestibular receptors, resulting from acute hypotension insult, are transmitted through group I mGluRs as well as AMPA and NMDA receptors in the vestibular system.

Roles of Metabotropic Glutamate Receptors 1 and 5 in Rat Medial Vestibular Nucleus Neurons

Using whole cell current- and voltage-clamp recording we investigated the characteristics and pharmacology of group I metabotropic glutamate receptor (mGluR)-mediated responses in rat medial vestibular nucleus (MVN) neurons. In current clamp conditions, activation of mGluR I by application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced a direct excitation of MVN neurons that is characterized by depolarization and increased spontaneous firing frequency. To identify which of mGluR subtypes are responsible for the various actions of DHPG in MVN, we used two subtype-selective antagonists. (S)-(+)-alpha-amino-a-methylbenzeneacetic acid (LY367385) is a potent competitive antagonist that is selective for mGluR1, whereas 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is a potent noncompetitive antagonist that is selective for mGluR5. In voltage clamp conditions, DHPG application increased the frequency of spontaneous and miniature inhibitory postsynaptic currents (IPSCs) but had no effect on amplitude distributions. Antagonism of the DHPG-induced increase of miniature IPSCs required the blockade of both mGluR1 and mGluR5. DHPG application induced an inward current, which can be enhanced under depolarized conditions. DHPG-induced current was blocked by LY367385, but not by MPEP. Both LY367385 and MPEP antagonized the DHPG-induced suppression of the calcium activated potassium current (IAHP). These data suggest that mGluR1 and mGluR5 have similar roles in the regulation of the excitability of MVN neurons, and show a little distinct. Furthermore, mGluR I, via pre- and postsynaptic actions, have the potential to modulate the functions of the MVN.

Microarray analysis of DHPG-induced rat hippocampal slice epileptic seizure model / 上海交通大学学报（医学版）

Objective To investigate the gene expression pattern of metabotropic glutamate receptor- Ⅰ ( mGluR-Ⅰ ), D-p-hydroxyphenylglycine (DHPG) -induced rat hippocampal slice epileptic seizure model. Methods In vitro rat hippocampal sclice was continously perfused with artificial cerebrospinal fluid containing 50 μmol DHPG, and epileptic seizure model was established (DHPG group, n = 3). cDNA microarray chip was applied to explore the gene expression pattern in DHPG group, the differentially expressed genes were screened in comparison with control group ( n = 3), and functional classification analysis was conducted. Results There were 206 up-regulated genes and 489 down-regulated genes, among which 67 up-regulated genes and 86 down-regulated genes differentially expressed by 1.5 fold, 6 up-regulated genes differentially expressed by more than 2.0 folds, and 25 down-regulated genes differentially expressed by less than 0.5 fold. Functional classification analysis revealed that differentially expressed gene function involved in protein binding (19 genes), molecular function, calcium ion binding and nucleotide binding. Conclusion Epileptic seizure and roles of mGluR-Ⅰ agonist may be related to various genes, which is a complicated process. This experiment provides evidences for further researches.

Glutamate enhances the expression of vascular endothelial growth factor in cultured SD rat astrocytes / 西安交通大学学报·英文版

Objective: To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods: Cultured rat astrocytes were randomly divided into 6 groups: control group (C), glutamate group (G), QA group (Q), DCG-IV group (D), L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air, 5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes, respectively. G+M group was preincubated with 1mM MCPG for 30 min prior to the stimulation with glutamate. There were 7 time points at 0, 4, 8, 12, 16, 24 and 48 h in each group except G+M group. Results: The expression of VEGF mRNA and protein did not differ significantly among D group, L group and C group. Different from that in C group, the expression of VEGF mRNA and protein could be enhanced both in a dose-dependent and time-dependent manner in G group and Q group. Meanwhile, the enhanced expression of VEGF mRNA and protein in G group was completely suppressed by MCPG after 24 h. Conclusion: Glutamate can increase the expression of VEGF mRNA and protein in cultured astrocytes, which may be due to the activation of group I metabotropic glutamate receptors in astrocytes.

Glutamate enhances the expression of vascular endothelial growth factor in cultured SD rat astrocytes / 药物分析学报

Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups: control group (C), glutamate group (G), QA group (Q), DCG-IV group (D), L-AP4 group (L) and glutanmte-FMCPG gronp (G+M). Cells were cultured under nomoxic condition (95% air, 5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes, respectively. G+ M group was preincubated with lmM MCPG for 30 min prior to the stimulation with glutamate. There were 7 time points at 0,4,8,12,16,24 and 48 h in each group except G+M group. Results The expression of VEGF mRNA and protein did not differ significantly among D group, L group and C group. Different from that in C group, the expression of VEGF mRNA and protein could be enhanced both in a dose-dependent and time-dependent manner in G group and Q group. Meanwhile, the enhanced expression of VEGF mRNA and protein in G group was completely suppressed by MCPG after 24 h. Conclusion Glutamate can increase the expression of VEGF mRNA and protein in cultured astrocytes, which may be due to the activation of group I metabotropic glutamate receptors in astrocytes.

Co-localization of metabotropic glutamate receptor 2 with ASIC3 or TRPV1 in the dorsal root / 神经解剖学杂志

Metabotropie glutamate receptor (mGluR) 2/3 plays an important role on the nociceptive transmission from periphery to spinal cord.The previous studies demonstrated that mGluR2 can contribute to mechanical hypersensitivity and thermal hypersensitivity in rat.Therefore,in the present study,by using the immunofluorescenee histochemical technique,we try to explore that whether mGluR2 is colocalized with acid-sensing ion channel 3 (ASIC3),a muhi-modulator of mechanosensation,or transient receptor potential/vanilloid receptor subtype-1 (TRPV1),which responses for thermosensation in dorsal root ganglion (DRG).Morphological observations showed that mGluR2-immunoreactivity was mainly distributed in cellular plasma of neurons in DRG.The counting number results indicated that 35.84% of DRG neurons were mGluR2-immunoreactive (ir).On the other hand,82.61% of mGluR2-ir cells were the small-diameter neurons (diameter:＜30 μm),5.79% of which were the medium-diameter neurons (diameter:30-50μm) and 11.59% of which was the large-diameter neurons (diameter:＞50 tun).Furthermore,42.45% and 79.78% of mGiuR2-ir cells was individually co-localized with ASIC3-or TRPVI-ir in small-diameter neurons in the double-labeled immunofluorescence sections.The present results suggest that mGhiR2 mainly exists in small neurons of the DRG,which are regarded as nociceptors consisting of AS-and C-fibers.While mGluR2 is highly co-localized with ASIC3 and TRPV1,implying their potential relationship in DRG may be involved in mechanical hypersensitivity and thermal hypersensitivity.

The Role of Metabotropic Glutamate Receptors in Psychomotor Stimulant Addiction / 대한정신약물학회지

For many years, determining the role of dopamine has been the major focus of the drug abuse research. New evidence, however, suggests that glutamate may play more important roles in the process of development of addictive behaviors. Metabotropic glutamate receptors are abundant in the brain and known to consist of three different groups of subtypes. Experimental data apparently show that they, especially group I and II, have important roles in the process of behaviors indicative of addiction such as locomotor activity, behavioral sensitization, conditioned place preference by psychomotor stimulants, and self-administration of these drugs. Although it has not been yet discovered how they differentially regulate neuronal processes to produce addictive behaviors, they have been suggested as a new possible therapeutic target for the treatment of drug addiction.

Roles of metabotropic glutamate receptors on excitatory synaptic transmission in rat trigeminal caudal neurons

Mechanism of Glutamate-inducedCa2+i Increase in Substantia Gelatinosa Neurons of Juvenile Rats

The glutamate receptors (GluRs) are key receptors for modulatory synaptic events in the central nervous system. It has been reported that glutamate increases the intracellularCa (2+) concentration ([Ca2+]i) and induces cytotoxicity. In the present study, we investigated whether the glutamate-induced[Ca2+]i increase was associated with the activation of ionotropic (iGluR) and metabotropic GluRs (mGluR) in substantia gelatinosa neurons, using spinal cord slice of juvenile rats (10~21 day) .[Ca2+]i was measured using conventional imaging techniques, which was combined with whole-cell patch clamp recording by incorporating fura-2 in the patch pipette. At physiological concentration of extracellularCa (2+), the inward current and[Ca2+]i increase were induced by membrane depolarization and application of glutamate. Dose-response relationship with glutamate was observed in bothCa (2+) signal and inward current. The glutamate-induced[Ca2+]i increase at holding potential of 70 mV was blocked by CNQX, an AMPA receptor blocker, but not by AP-5, a NMDA receptor blocker. The glutamate-induced[Ca2+]i increase inCa (2+) free condition was not affected by iGluR blockers. A selective mGluR (group I) agonist, RS-3, 5-dihydroxyphenylglycine (DHPG), induced[Ca2+]i increase at holding potential of 70 mV in SG neurons. These findings suggest that the glutamate-induced[Ca2+]i increase is associated with AMPA-sensitive iGluR and group I mGluR in SG neurons of rats.

Regulation of dopamine and glutamate release by metabotropic glutamate receptors in the basal ganglia motor circuit:implications for treatment of parkinsons disease / 中国药理学通报

Metabotropic glutamate receptors (mGluRs) are a family of G protein coupled receptors linked to modulation of ion channel functions and multiple second messengers. These receptors are widely distributed throughout the basal ganglia (BG). Studies have demonstrated that these mGluRs subtypes located at various synapses in BG could modulate the release of dopamine and glutamate which correlates with brain area,the subtype selectivity and concentration of the ligands. Metab otropic glutamate receptors have been proposed as potentially new therapeutic targets for Parkinsons disease by providing a method of pharmacologically regulating neurotransmission in the BG.