mGluR Research Articles

Effect of low-dose ketamine combined with propofol anesthesia on expression of GluR1 and GABAA R in hippocampus after electroconvulsive therapy in depressed rats

Objective To evaluate the effects of low-dose ketamine combined with propofol anesthesia on the expression of glutamate receptor 1 (GluR1) and γ-aminobutyric acid type A receptor (GABAA R) in hippocampus after electroconvulsive therapy (ECT) in depressed rats.Methods Fifty healthy adult male SpragueDawley rats,aged 2-3 months,weighing 200-250 g,were used in this study.The depressed model was induced by chronic unpredictable mild stress (CUMS).The mentally depressed rats were randomly divided into 5 groups (n =10 each):depression group (group D),ECT group,ketamine + ECT group (group KE),propofol + ECTgroup (group PE) and ketamine + propofol + ECT group (group KPE).Group ECT received ECT once a day for 7 consecutive days after intraperitoneal injection of normal saline 8 ml/kg.KE,PEK and KPE groups received ECT once a day for 7 consecutive days after intraperitoneal injection of ketamine 10 mg/kg,propofol 100 mg/kg,and ketamine 10 mg/kg + propofol 80 mg/kg,respectively.Sucrose fluid consumption was performed before CUMS,at 1 day after CUMS and at 1 day after ECT.The rats were sacrificed and hippocampi were removed for determination of the expression of GluR1 and GABAA R (by immuno-histochemistry).The GluR1/GABAA R ratio was calculated.Results Compared with group D,the sucrose consumption percentage was significantly increased at 1 day after ECT,the expression of GluR1 in hippocampal CA1 and CA3 regions was up-regulated,and the GluR1/GABAA Rratio was increased in the other four groups,and the expression of GABAA R in hippocampal CA1 and CA3 regions was down-regulated in ECT,PE and KPE groups (P ＜ 0.05).Compared with ECT group,the sucrose consumption percentage was significantly increased at 1 day after ECT,the expression of GABAA R and GluR1 in hippocampal CA1 and CA3 regions was up-regulated,and the GluR1/GABAA R ratio was increased in KPE group,the expression of GluR1 and GABAA R in hippocampal CA1 and CA3 regions was up-regulated in KE group,and the expression of GABAA R in hippocampal CA1 and CA3 regions was down-regulated in PE group (P ＜ 0.05).Compared with group PE,the sucrose consumption percentage was significantly increased at 1 day after ECT,the expression of GluR1 and GABAAR in hippocampal CA1 and CA3 regions was up-regulated,and the GluR1/GABAA R ratio was increased in KPE group (P ＜ 0.05).Conclusion The mechanism by which low-dose ketamine combined with propofol enhances the efficacy of ECT in depressed rats may be related to better regulation of the balance between hippocampal GluR1 and GABAA R. Key words: Depression; Ketamine ; Propofol ; Electroconvulsive therapy ; Receptors, AMPA ; Receptors, GABA-A; Hippocampus

The effect of acupuncture on AMPA receptor expression in the hippocampus of senescence-accelerated mice is correlated with synaptic plasticity

Objective To observe any effect of acupuncture on AMPA receptor expression and synaptic plasticity in the hippocampal neurons of mice prone to accelerated senescence (SAMP8s).Methods Nineteen SAMP8s aged 9 months were randomly divided into a model group (n =10) and an acupuncture group (n =9).Nine mice resistant to accelerated senescence (SAMR1s) were used as a control group.Acupuncture was administered daily on the DU20 (Baihui) and K1 (Yongquan) acupoints,7 days in each course for 4 courses,with a 2 day interval between courses.The Morris water maze was used to observe learning and memory abilities.The mice were sacrificed after the last treatment.Transmission electron microscopy was used to observe the synaptic ultrastructure in subregion CA1 of the hippocampus.Western blotting was used to detect the expression of the AMPA receptor subunits GluR1 and GluR2.Results Compared to the control group,escaping latency was prolonged significantly in the model group but decreased in the acupuncture group.Target annulus crossings decreased significantly in the model group but increased significantly in the acupuncture group.Compared to the model group,the average thickness of the post-synaptic density (PSD) and the curvature of the synaptic interface both increased significantly in the acupuncture group,while the average synapse width decreased significantly.There were no significant differences in GluR1 expression among the groups,but compared to the control group,GluR2 expression decreased significantly in the model group but was significantly up-regulated in the acupuncture group.Conclusions Acupuncture can improve learning and memory,facilitate synaptic plasticity and up-regulate GluR2 expression in hippocampal neurons,at least among SAMP8 rats. Key words: Acupuncture therapy; Learning; Memory; Synaptic plasticity; AMPA receptors; Senescence

Palmitoylation of Estrogen Receptors Is Essential for Neuronal Membrane Signaling

In addition to activating nuclear estrogen receptor signaling, 17β-estradiol can also regulate neuronal function via surface membrane receptors. In various brain regions, these actions are mediated by the direct association of estrogen receptors (ERs) activating metabotropic glutamate receptors (mGluRs). These ER/mGluR signaling partners are organized into discrete functional microdomains via caveolin proteins. A central question that remains concerns the underlying mechanism by which these subpopulations of ERs are targeted to the surface membrane. One candidate mechanism is S-palmitoylation, a posttranscriptional modification that affects the subcellular distribution and function of the modified protein, including promoting localization to membranes. Here we test for the role of palmitoylation and the necessity of specific palmitoylacyltransferase proteins in neuronal membrane ER action. In hippocampal neurons, pharmacological inhibition of palmitoylation eliminated 17β-estradiol-mediated phosphorylation of cAMP response element-binding protein, a process dependent on surface membrane ERs. In addition, mutation of the palmitoylation site on estrogen receptor (ER) α blocks ERα-mediated cAMP response element-binding protein phosphorylation. Similar results were obtained after mutation of the palmitoylation site on ERβ. Importantly, mutation of either ERα or ERβ did not affect the ability of the reciprocal ER to signal at the membrane. In contrast, membrane ERα and ERβ signaling were both dependent on the expression of the palmitoylacyltransferase proteins DHHC-7 and DHHC-21. Neither mGluR activity nor caveolin or ER expression was affected by knockdown of DHHC-7 and DHHC-21. These data collectively suggest discrete mechanisms that regulate specific isoform or global membrane ER signaling in neurons separate from mGluR activity or nuclear ER function.

Effects of electroacupuncture on expression of PKC mRNA, mGluRs and AMPAR in hippocampus of rats with vascular dementia

Objective To observe the effect of electroacupuncture on the hippocampal PKC mRNA,mGluRs and AMPAR expression in rats with vascular dementia (VD),so as to explore the underlying mechanisms of electroacupuncture (EA) therapy for VD.Methods Thirty Sprague-Dawley rats were randomly divided into a sham-operation group,a model group and an EA group(10 in each group).VD model was established by repeated ischemia/reperfusion.Then the rats were placed in the rat fixer with their heads and back exposed.The electro-acupuncture were superficially inserted into “ Baihui” (GV20) and “ Dazhui” (DU14) in rats.EA was applied to “Baihui” (GV20),“Dazhui” (DU14) in EA group for 20 min,once daily for 10 days.The PKC mRNA,mGluRs and AMPAR expression in hippocampal tissue were examined by RT-PCR and immunohistochemical assay.Results The expression level of PKC mRNA in hippocampus of the model group was lower than that of the shamoperation group.Compared with the model group,the level of PKC mRNA was significantly increased in the EA group (P ＜ 0.05).The mGluRs immunoreactive cell integrated optical density (IOD) in hippocampus in the sham-operation group,the model group and the EA group were (58.6 ±3.6),(36.3 ±2.5) and (51.5 ±4.8),respectively; the mGluRs immunoreactive cell IOD in hippocampus in the model group was reduced significantly (P ＜0.01) when compared with the sham-operation group,The mGluRs immunoreactive cell IOD in hippocampus in the EA group was increased significantly as compared with the model group (P ＜ 0.05).AMPAR immunoreactive cell IOD in hippocampus in the sham-operation,the model group and the EA group were (66.5 ± 2.8),(40.1 ± 5.1) and (58.3 ± 4.6),respectively,and compared with the sham-operation group,the AMPAR immunoreactive cell IOD in hippocampus in the model group was reduced significantly.The difference of the AMPAR immunoreactive cell IOD in hippocampus between the sham-operation group and the model group were statistically significant (P ＜0.01) ; and compared with the model group,the AMPAR immunoreactive cell IOD in hippocampus in the EA group was increased significantly.The difference of the AMPAR immunoreactive cell IOD in hippocampus between the model group and EA group was statistically significant (P ＜0.05).Conclusion EA can enhance the expression of PKC mRNA,mGluRs and AMPAR.These results may contribute to the therapeutic effects of electroacupuncture on VD rats. Key words: Vascular dementia; Electroacupuncture; PKC mRNA; mGluRs; AMPAR

Role of Stargazin in trafficking of GluRl-containing AMPA receptors from cytoplasm to cell membrane in spinal dorsal horn in rats with incisional pain

Objective To evaluate the role of Stargazin in trafficking of GluR1-containing AMPA receptors from cytoplasm to cell membrane in the spinal dorsal horn in rats with incisional pain.Methods Forty-five adult male Sprague-Dawley rats,aged 6-8 yr,weighing 280-300 g,were randomly divided into 5 groups (n =9 each):control group (group C),sham operation group (group S),incisional pain + normal saline group (group P),incisional pain + Stargazin small interference RNA (siRNA) group (group Ⅰ),and incisional pain + non-sense siRNA group (group N).In P,I and N groups,normal saline 10 μl,20 μmol/L siRNA and 20 μmol/L non-siRNA 10 μl were injected intrathecally,respectively,twice a day for 3 consecutive days.A 1 cm long incision was made in the plantar surface of right hindpaw.Cumulative pain score (CPS) and paw-withdrawal threshold to yon Frey stimuli (PWT) were measured at 3 h after incision.The animals were sacrificed after pain behavior assessment.Their lumbar segments of the spinal cord (L3-6) were removed.The expression of GluR1 and GluR2 in cell membrane and cytoplasm in spinal cord dorsal horn was determined by Western blot analysis.The co-expression of Stargazin with GluR1 and GluR2 in the spinal dorsal horn was examined by co-immuno-precipitation.Results Compared with group C,the CPS was significantly increased,the PWT was decreased,the expression of GluR1 in cytoplasm was down-regulated and the expression of GluR1 in cell membrane was up-regulated in N and P groups,and the CPS was increasedin group Ⅰ (P ＜ 0.05 or 0.01).Compared with group P,the CPS was significantly decreased,the PWT was increased,the expression of GluR1 in cytoplasm was up-regulated,the expression of GluR1 in cell membrane was down-regulated,and the expression of Stargazin and co-expression of Stargazin with GluR1 and GluR2 in the spinal dorsal horn was down-regulated in group Ⅰ (P ＜ 0.05 or 0.01).Conclusion Stargazin mediates trafficking of GluR1-containing AMPA receptors from cytoplasm to cell membrane in spinal dorsal horn and is involved in the development of hyperalgesia in rats with incisional pain. Key words: Receptors, AMPA; Protein transport; Pain; Spinal cord; Stargazin

Changes in expression of GluR1-containing AMPA receptor and GluR2-containing AMPA receptor in spinal dorsal horn in a rat model of incisional pain-remifentanil-induced hyperalgesia

Objective To investigate the changes in the expression of GluR1-containing AMPA receptor and GluR2-containing AMPA receptor in spinal dorsal horn in a rat model of incisional pain-remifentanil-induced hyperalgesia.Methods Thirty-two male Sprague-Dawley rats,aged 2-3 months,weighing 240-260 g,in which the catheter was successfully inserted into the caudal vein,were randomly divided into 4 groups (n =8 each):control gourp (group C),remifentanil group (group R),incisional pain group (group P),and remifentanil + incisional pain group (group R + I).A 1-cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the left hindpaw in chloral hydrate-anesthetized rats.Remifentanil 1.0 μg· kg-1 · min-1 was infused intravenously for 1 h sarting from beginning of establishment of incisional pain model.Paw withdrawal threshold (PWT) to yon Frey hair stimulation and paw withdrawal latency (PWL) to thermal stimulation were measured before remifentanil infusion and at 2,6,24 and 48 h after remifentanil infusion.The rats were sacrificed after the last behavioral test and L4-6 segments of the spinal cord were removed for determination of the expression of AMPA receptor GluR1 and GluR2 subunits in total and membrane protein in the dorsal horn of spinal cord by Western blot.The ratio between the expression of GluR1 and GluR2 subunits in membrane protein (GluR1/GluR2) was calculated.Results Compared with group C,PWL was significantly shortened,PWT was decreased,the expression of GluR1 in total and membrane protein was up-regulated,the expression of GluR2 in total and membrane protein was down-regulated,and GluR1/GluR2 ratio was increased in I,R and R + I groups (P ＜ 0.05).Compared with R and I groups,PWL was significantly shortened,PWT was decreased,the expression of GluR1 in total and membrane protein was up-regulated,the expression of GluR2 in total and membrane protein was down-regulated,and GluR1/GluR2 ratio was increased in group R + I (P ＜ 0.01).Conclusion Increased percentage of GluR1-conraining AMPA receptors in membrane protein induced by up-regulation of expression of GluR1-containing AMPA receptor and down-regulation of expression of GluR2-containing AMPA receptor in total and membrane protein is involved in the development of incisional pain-remifentanil-induced hyperalgesia in rats. Key words: Receptors, AMPA; Piperidines; Hyperalgesia; Pain; Spinal cord

Role of PI3K-AMPA receptor subunit glutamate receptor 2 pathway in propofol postconditioning-induced reduction of cerebral ischemia-reperfusion injury in rats

Objective To evaluate the role of phosphatidyl-inositol 3 kinase （PI3K）-α-amino-3-hydroxy- 5-methylisoxazole-4-propionic acid （AMPA） receptor subunit glutamate receptor 2 （GluR2） pathway in propofol postconditioning-induced reduction of cerebral ischemia-reperfusion （I/R） injury in rats. Methods One hundred and eighty male Sprague-Dawley rats, weighing 250-280 g, were randomly divided into 5 groups with 36 rats in each group： sham operation group （group S）, I/R group, propofol postconditioning group （group P）, intralipid posteonditioning group （group I）, and PI3K inhibitor wortmannin ＋ propofol postconditioning group （group W ＋ P）. The rats were anesthetized with intraperitoneal 10% chloral hydrate 350 mg/kg. Cerebral I/R was produced by 60 min middle cerebral artery occlusion followed by reperfusion. Propofol and 10% intralipid were infused via the femoral vein at a rate of 20 mg. kg- 1. h -1 for 2 h starting from the onset of reperfusion in groups P and I, respec- tively, while the equal volume of normal saline was given instead in groups I/R and S. Wortmannin 0.6 mg/kg wasinjected intraperitoneally at 30 min before reperfusion in group W ＋ P. The modified Neurological Severity Score （mNSS） was assessed and the cerebral infarct volume was detected at 12 and 24 h after operation. The hippocampi on the ischemie side were obtained at 4, 6, 12 and 24 h after operation for determination of expression of PI3K- GluR2-containing AMPA receptor （by co-immunopreeipitation and Western blot） and activity of PI3K （by ELISA）. Results Compared with group S, the mNSSs and infarct volume were significantly increased at 12 and 24 h after operation, and the activity of PI3K was decreased, and the expression of PI3K-GluR2-eontaining AMPA re- ceptor was down-regulated at 4, 6, 12 and 24 h after operation in the other four groups （ P 〈 0.05）. Compared with group I/R, the mNSSs and infarct volume were significantly decreased at 12 and 24 h after operation, and the activity of PI3K was increased, and the expression of PI3K-GluR2-containing AMPA receptor was up-regulated at 4, 6, 12 and 24 h after operation in group P （ P 〈 0.05） . Compared with group W ＋ P, no significant change was found in the parameters mentioned above in groups I/R and I （P 〉 0.05）, and the mNSSs and infarct volume were significantly decreased at 12 and 24 h after operation, and the activity of PI3K was increased, and the expression of PI3K-GluR2-containing AMPA receptor was up-regulated at 4, 6, 12 and 24 h after operation in group P （ P 〈 0.05 ）. Conclusion PI3K-AMPA receptor subunit GluR2 pathway is involved in propofol posteonditioning-indueed reduction of cerebral I/R injury in rats. Key words: 1-phosphatidylinositol 3- kinase ; Receptors, AMPA ; Propofol ; Reperfusion injury ; Brain ; Postconditioning

Effects of propofol on phosphorylation of AMPA receptor GluR1 subunits in a rat model of visceral pain

Objective To investigate the effects of propofol on the phosphoryhtion of α-amino-3-hydroxy5-methyl-4-isoxazolepropionate(AMPA)receptor GluR1 subunits at Serine-831 and Serine-845 sites in the spinal cord dorsal horn in a rat model of visceral pain.Methods Thirty male SD rars,aged 6-8 weeks,weighing 200300 g,in which intrathecal catheters were successfully placed without complications,were randomly divided into 3 groups(n-=10 each):sham operation group(group Ⅰ),visceral pain group(group Ⅱ)and propofol group (group Ⅲ).Visceral pain was induced by injection of 10％ capsaicin 50μl via the rectum in groups Ⅱ and Ⅲ.While the equal volume of normal saline was given instead in group Ⅰ.Group Ⅲ received intrathecal injection of propofol 20 tg at 10 min before injection of capsaicin.While the equal volume of dimethyl sulfoxide was given instead of propofol in groups Ⅰ and Ⅱ.The cumulative pain score was recorded during 30 min after capsaicin injection.The rats were then sacrificed,and the lumbar segment(L3-6)of the spinal cord was removed for determination of the expression of GluR1 subunits and phosphorylation of GluR1 subunits at Serine-831 and Serine-845 sites in the spinal cord dorsal horn.Results Compared with group Ⅰ,the cumulative pain score and phosphorylation of GluR1 subunits at Serine-831 sites and Serine-845 in the spinal cord dorsal horn were significantly increased(P ＜0.05 or 0.01),but there were no significant differences in the expression of GluR1 subunits in groups Ⅱ and Ⅲ (P ＞ 0.05).Compared with group Ⅱ,the cumulative pain score and phosphorylation of GluRl subunits at Serine831 and Serine-845 sites in the spinal cord dorsal horn were significantly decreased in group Ⅲ(P ＜ 0.05 or 0.01).Conclusion Propofol can attenuate the visceral pain through the inhibition of the phosphorylation of AMPA receptor GluR1 subunits at Serine-831 and Serine-845 sites in tte rat spinal cord dorsal horn. Key words: Propofol; Receptors,AMPA; Spinal cord; Pain

The N-Methyl-D-Aspartic Acid Receptor Antagonist Memantine Ameliorates and Delays the Development of Arthritis by Enhancing Regulatory T Cells

The neuroendocrine impact on rheumatoid arthritis is not yet fully described although numerous neurotransmitters are shown to act as inflammatory modulators. One of these is the excitatory transmitter glutamate (Glu). In this study, the influence of the Glu receptor (GluR)-mediated effects on collagen-induced arthritis (CIA) was investigated. CIA was induced in DBA/1 mice by immunization with chicken collagen type II (CII). Mice were exposed to the following GluR antagonists: group 1, the N-methyl-D-aspartic acid (NMDA) receptor channel blocker memantine; group 2, the metabotropic GluR antagonist AIDA, and group 3, the excitatory amino acid receptor antagonist kynurenic acid (KA). Arthritis was evaluated clinically and histologically and compared to PBS-treated controls. The effects of treatment on T cell populations and the levels of anti-CII and anti-citrullinated peptide antibodies were evaluated. Memantine treatment significantly improved the course of CIA, reducing synovitis (p = 0.007) and the frequency of erosions (p = 0.007). Memantine treatment up-regulated the expression of Foxp3 in spleen CD4+ T cells followed by an increase in CD4+CD25+ regulatory T cells. The other GluR antagonists, AIDA and KA, had no effect on CIA. These results demonstrate that blockade of the NMDA receptor channel with memantine delays and attenuates the development of arthritis, probably by promoting the development of regulatory T lymphocytes.

Influence of bone marrow mesenchymal stem cells transplantation on the expression of AMPA receptor protein in rats with spinal cord injury

Objective To observe the influence of bone marrow mesenchymal stem cells (BMSCs) transplantation on the expression of alpha-amino hydroxymethyl-oxazole propionic acid (AMPA) receptors GluR1 and GluR2 in rats with spinal cord injury (SCI) so as to investigate the potential anti- chronic stress mechanism of BMSCs transplantation in treatment of rats with spinal cord injury.Methods A total of 48 adult male SD rats were equally divided into three groups:control group,treatment group and model group.The rats in the model and treatment group underwent lower thoracic SCI with the modified Allen' s method,and the rats in control group received only laminectomy.At day 7 after thoracic SCI,100 μl of Hank's buffered saline solution containing 1.0 × 106 BMSCs was injected into the subarachnoid space from L4-L5 intervertebral space in the treatment group and control group,and the same amount of Hank' s buffered saline solution was injected in the model group.The motor function of the rat posterior limbs was assessed by Basso-Beattie-Bresnahan (BBB) scale before and after operation.Half of the rats were anesthetized at days 14 and 28 postoperatively to harvest brains which were frozen and cut in a cryostat to detect the expressions of GluR1 and GluR2 proteins by immunohistochemistry.Results After BMSCs transplantation,the motor function of the posterior limbs in the treatment group was improved progressively.At day 14 after transplantation,the number of GluR1-positive cells of the model and treatment group was higher than that of the control group in the hippocampus CA1 region (P ＜0.05,P ＜0.01 respectively) ; GluR2-positive cells had the similar tendency,without significant difference(P ＞ 0.05 ).At the 28th day after transplantation,GluR1 positive cells of the model group were higher than those of the control group in CA1,CA3,DG regions and those of the treatment group in CA1,CA3 regions (P ＜0.05,P ＜0.01,respectively) ; GluR1 positive cells of the model and treatment group were higher than their counterpart at day 14 after grafting procedure,with significant difference (P ＜0.05,P ＜0.01,respectively).GluR2 positive cells of the treatment group were higher than those of the control group in the basolateral amygdale (BLA) (P ＜0.05 ) and had similar tendency with GluR1 expression in other regions ( P ＞ 0.05 ).Conclusion BMSCs transplantation implies a potential antichronic stress mechanism of SCI rats,since it can improve the motor function of posterior limbs in rats with lower thoracic SCI and regulate the expressions of AMPA receptor GluR1 and GluR2. Key words: Spinal cord injury; Bone mesenchymal stem cells; Receptoos, glutamate

How to find a needle in a haystack? The application of in silico methods in searching of potentially new PAM of mGluR III

How to find a needle in a haystack? The application of in silico methods in searching of potentially new PAM of mGluR III

The research on the property of GluR1 subunit in rat models of motor complication of Parkinson' s disease after CaMKII inhibitor KN-93 treatment

Objective To investigate the alteration of phosphorylated GluR1Ser831 and behavioural effects in a rat model of levodopa-induced motor complications after Ca2 +/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) inhibitor KN-93 treatment. Methods The hemi-parkinsonian rat model was produced by injecting stereotaxically 6-OHDA to right medial forebrain bundle. Then, rats were intraperitoneally treated with levodopa ( 50 mg/kg with benserazide 12.5 mg/kg,twice daily) for 22 days. On day 23 ,rats received KN-93 before levodopa administration. Rotational duration was estimated. After sacrificed, subcellualr distribution of GluR1 and phosphorylated GluR1Ser831 were observed by western blot. Results The study showed that CaMKⅡ inhibitor KN-93 prolonged rotational duration. Moreover, KN-93 could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser831, which was closely associated with levodopa-induced motor complications. The expression of membrane GluR1 and phosphorylated GluR1Ser831 was (83.4 ±4.2)% and (47.2 ±5.2)% ,respectively. Conclusions These results indicated that activation of CaMKⅡ contributed to development of motor complications, through a mechanism that involved an increase in phosphorylated GluR1 Ser831. Pharmaceuticals which act to inhibit CaMKⅡ may be useful in the treatment of the motor complications in parkinsonian patients. Key words: Parkinson' s disease; Motor complication; Glutamate receptor (GluR); Phosphorylation; Ca2 +/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)

Theoretical Considerations on the Topological Organization of Receptor Mosaics

The concept of Receptor Mosaic (RM) is discussed; hence the integrative functions of the assemblage of G-protein coupled receptors physically interacting in the plane of the plasma membrane. The main focus is on a hetero-trimer of G-protein coupled receptors, namely the A2A-D2-CB1 receptor trimer. A bioinformatics analysis was carried out on the amino acid sequence of these receptors to indicate domains possibly involved in the receptor-receptor interactions. Such a bioinformatic analysis was also carried out on the RM formed by mGLU R5, D2 and A2A. The importance of topology, i.e., of the reciprocal localisation of the three interacting receptors in the plan of the membrane for the RM integrative functions is underlined. However, it is also pointed out that this fundamental aspect still waits techniques capable of an appropriate investigation. Finally, it is discussed how RM topology can give hints for a structural definition of the concept of hub receptor. Thus, just as in any network, the receptor operating as a hub is the one that in the molecular network formed by the receptors has the highest number of inputs.

Expression of metabotropic glutamate receptor 5 in spinal cord of morphine tolerant rats

To investigate the expression of metabotropic glutamate receptor 5 (mGluRS) in spinal cord of morphine tolerant rats and understand the influence of mGluR5 antagonist MPEP upon the expression of mGluRS. Male Sprague-Dawley rats were randomly divided into four groups with 8 rats each:control group (NS), morphine group, morphine plus MPEP group and MPEP group. A morphine tolerance model of rat was established by repeated administration of 10 microg morphine intrathecally twice daily for 7 days. The effects of morphine co-administrated with MPEP upon the thermal pain threshold were examined by tail flick test. Tail flick latency (TFL) was measured at 30 min pre- and postdosing. MPE% (percentage of maximal possible effect) was calculated by the equation: MPE (%) = [(test response time-basal response time)/(cut-off time-basal response time)] x 100%. The rats were sacrificed and L4-5 spinal cord tissue was removed. The expression of mGluR5 in every group was examined by immunofluorescence and Western blot. MPE% of morphine group decreased gradually after chronic administration of morphine intrathecally. There was no significant difference between morphine group and control group at Day 7 (P > 0.05). Morphine plus MPEP group had significant analgesic effect as compared with morphine group at Day 7 (P < 0.05). The expression of mGluR5 was up-regulated in the dorsal horn of spinal cord in morphine tolerant rats. The protein level of mGluRS in morphine plus MPEP group was lower than that in morphine group (P < 0.05), but higher than control group (P < 0.05). The mGluR5 antagonist MPEP can prevent the development of morphine tolerance. The expression of mGluR5 protein increases in the spinal cord of morphine tolerant rats. MPEP plays its role in morphine tolerance by partly inhibiting the expression of mGluRS.

Involvement of metabotropic glutamate receptor in morphine tolerance and dependence

Glutamate mediates its effects via both ionotropie and metabotropic receptors. Metabotropic glutamate receptors (mGluRs) include eight subtypes and are classified into three major groups. G protein-coupled mGluRs modulate function of ion channel, neurotransmitter releasing, synapse transmission and plasticity through pre-and post-synaptic sites. Recent evidence supports the involvement of mGluRs in the development of morphine tolerance and dependence. This article reviewed the progress in differential role of mGluRs subtypes in morphine tolerance and dependence. Key words: Glutamate ; Metabotropic glutamate receptor ; Morphine tolerance ;

Capsaicin-Induced Glutamate Release Is Implicated in Nociceptive Processing Through Activation of Ionotropic Glutamate Receptors and Group I Metabotropic Glutamate Receptor in Primary Afferent Fibers

Glutamate (Glu) is the major excitatory neurotransmitter in the central nervous system. The role of peripheral Glu and Glu receptors (GluRs) in nociceptive transmission is, however, still unclear. In the present study, we examined Glu levels released in the subcutaneous perfusate of the rat hind instep using a microdialysis catheter and the thermal withdrawal latency using the Plantar Test following injection of drugs associated with GluRs with/without capsaicin into the hindpaw. The injection of capsaicin into the rat hind instep caused an increase of Glu level in the s.c. perfusate. Capsaicin also significantly decreased withdrawal latency to irradiation. These effects of capsaicin were inhibited by pretreatment with capsazepine, a transient receptor potential vanilloid receptor 1 (TRPV1) competitive antagonist. Capsaicin-induced Glu release was also suppressed by combination with each antagonist of ionotropic GluRs (iGluRs: NMDA/AMPA receptors) and group I metabotropic GluR (mGluR), but not group II and group III mGluRs. Furthermore, these GluRs antagonists showed remarkable inhibition against capsaicin-induced thermal hyperalgesia. These results suggest that Glu is released from the peripheral endings of small-diameter afferent fibers by noxious stimulation and then activates peripheral iGluRs and group I mGluR in development and/or maintenance of nociception. Furthermore, the activation of peripheral NMDA/AMPA receptors and group I mGluR may be important in mechanisms whereby capsaicin evokes nociceptive responses.

A δ-Catenin Signaling Pathway Leading to Dendritic Protrusions

Delta-catenin is a synaptic adherens junction protein pivotally positioned to serve as a signaling sensor and integrator. Expression of delta-catenin induces filopodia-like protrusions in neurons. Here we show that the small GTPases of the Rho family act coordinately as downstream effectors of delta-catenin. A dominant negative Rac prevented delta-catenin-induced protrusions, and Cdc42 activity was dramatically increased by delta-catenin expression. A kinase dead LIMK (LIM kinase) and a mutant Cofilin also prevented delta-catenin-induced protrusions. To link the effects of delta-catenin to a physiological pathway, we noted that (S)-3,5-dihydroxyphenylglycine (DHPG) activation of metabotropic glutamate receptors induced dendritic protrusions that are very similar to those induced by delta-catenin. Furthermore, delta-catenin RNA-mediated interference can block the induction of dendritic protrusions by DHPG. Interestingly, DHPG dissociated PSD-95 and N-cadherin from the delta-catenin complex, increased the association of delta-catenin with Cortactin, and induced the phosphorylation of delta-catenin within the sites that bind to these protein partners.

The research progress of Homer1a

Homerl a is a short form Homer protein that is the member of the PSD proteins. This product of neuronal immediate early gene is rapidly and transiently induced by physiological synaptic activity. Long - form Homer proteins and Shank proteins bind to and colocalize with mGluRs, iGluRs and other functionally synaptic proteins, which can be antagonized by the short, activity - dependent splice variant -Homerla. Homerl a affects critically in the signal transduction, distribution and orientation of receptors, the synaptogenesis, the functions and plasticity of synapse. Recently, we are paying our attention to its influence on signal transmission and promising therapeutic target for the treatment of pain. Key words: homerla; IEG; mGluR Ⅰ ; NMDAR; pain

Effect of ketogenic diet on hippocampus mossy fiber sprouting and GluR5 expression in kainic acid induced rat model

Ketogenic 饮食(KD ) 是高胖的、低蛋白质，低糖类饮食。Itsantiepileptic 效果肯定，但是内在的机制是未知的。苔状的纤维在有牙齿的回转的内部分子的层发芽在马头鱼尾的怪兽引起 synaptic 重组，它是在动物和人的时间的脑叶癫痫的一个重要原因。它对癫痫的开始和发展也必要。作为在中央神经系统的占优势的 excitatoryneurotrans 棒球手套，充斥使挫折在 synaptic 重组和癫痫的开发起一个作用。在最近的年里，角色充斥(GluR_5 ) 使挫折受体 5 在发作的开始吸引了研究人员的越来越多的注意，这受体成为了新镇癫痫剂药的一个候选人目标。在这研究，我们以 synaptic 重组和 GluR_5 表示调查了 KD 的可能的镇癫痫剂机制，试图提供新镇癫痫剂药的发展的一个理论基础。

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Activity-dependent regulation of synaptic AMPA receptor (AMPAR) number is critical to NMDA receptor (NMDAR)-dependent synaptic plasticity. Using quantitative high-resolution in situ hybridization, we show that mRNAs encoding the AMPA-type glutamate receptor subunits (GluRs) 1 and 2 are localized to dendrites of hippocampal neurons and are regulated by paradigms that alter synaptic efficacy. A substantial fraction of synaptic sites contain AMPAR mRNA, consistent with strategic positioning and availability for "on-site" protein synthesis. NMDAR activation depletes dendritic levels of AMPAR mRNAs. The decrease in mRNA occurs via rise in intracellular Ca2+, activation of extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, and transcriptional arrest at the level of the nucleus. The decrease in mRNA is accompanied by a long-lasting reduction in synaptic AMPAR number, consistent with reduced synaptic efficacy. In contrast, group I metabotropic GluR signaling promotes microtubule-based trafficking of existing AMPAR mRNAs from the soma to dendrites. Bidirectional regulation of dendritic mRNA abundance represents a potentially powerful means to effect long-lasting changes in synaptic strength.