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Search Results: 1 - 10 of 4092 matches for " metabotropic receptor "
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IL-10 Gene Knockout Reduces the Expression of mGlu Receptor 1a/b and Decreases the Glutamate-Dependent Production of Nitric Oxide  [PDF]
Sopiko Koriauli, Tamar Barbakadze, Nino Natsvlishvili, Nino Dabrundashvili, Eka Kvaratskhelia, David Mikeladze
Journal of Biomedical Science and Engineering (JBiSE) , 2014, DOI: 10.4236/jbise.2014.713099
Abstract: IL-10 provides trophic and survival effects directly on neurons, promotes axonal outgrowth, and stimulates neuroregeneration. In this study, we analyzed the activities of arginase and nitric oxide synthase (NOS) in synaptoneurosomes derived from brain cortex of C57BL/6 IL-10 gene-knockout (KO) and wild-type (Wt) mice and determined that the synaptoneurosomes derived from KO mice present lower arginase II activity and lower spermine content than those derived from Wt mice, whereas the basal NOS activity in the KO synaptoneurosomes was higher than that observed in the control synaptoneurosomes. Moreover, our results indicate that the plasma membranes isolated from the KO mice brain exhibit significantly lower spermine-induced enhancement of [3H] MK-801 binding than the plasma membranes from the brain of Wt mice. Glutamate increases the production of nitric oxide (NO) in Wt synaptoneurosomes in a dose-dependent manner, whereas in the KO synaptoneurosomes, this amino acid does not affect the synthesis of NO. The glutamate-dependent acceleration of NO synthesis in Wt synaptoneurosomes was abrogated by LY367385, an antagonist of mGluR1a/b. The western blot analysis of the synaptoneurosomal proteins demonstrates that the expression of the subunits of NMDAR (NMDAR2A and NMDAR2B), the level of NMDAR-bound nNOS and the expression of iNOS are not changed in KO mice and that only the level of mGluR1a/b is markedly reduced in the synaptoneurosomes of KO mice. We conclude that a neuroprotective and neuroregenerative property of IL-10, in addition to its effects on polyamine metabolism and the spermine-dependent modulation of NMDAR, may involve the regulation of mGluR1a/b expression.
Functional and evolutionary aspects of chemoreceptors
Dieter Wicher
Frontiers in Cellular Neuroscience , 2012, DOI: 10.3389/fncel.2012.00048
Abstract: The perception and processing of chemical signals from the environment is essential for any living systems and is most probably the first sense developed in life. This perspective discusses the physical limits of chemoreception and gives an overview on the receptor types developed during evolution to detect chemical signals from the outside world of an organism. It discusses the interaction of chemoreceptors with downstream signaling elements, especially the interaction between electrical and chemical signaling. It is further considered how the primary chemosignal is appropriately amplified. Three examples of chemosensory systems illustrate different strategies of such amplification.
Differential Expression of mGluR2 in the Developing Cerebral Cortex of the Mouse  [PDF]
Pooja S. Venkatadri, Charles C. Lee
Journal of Biomedical Science and Engineering (JBiSE) , 2014, DOI: 10.4236/jbise.2014.713100
Abstract: Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabo-tropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.
Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception
Lara W Crock, Kristina M Stemler, David G Song, Philip Abbosh, Sherri K Vogt, Chang-Shen Qiu, H Henry Lai, Indira U Mysorekar, Robert W Gereau IV
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-20
Abstract: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice.Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.Interstitial cystitis/painful bladder syndrome (IC/PBS) is a serious and painful condition of unknown etiology that affects 3-6% of women in the United States [1,2]. The major clinical symptom of IC/PBS is pain upon bladder filling (distention) leading to urinary frequency and urinary urgency [3]. The current available treatments are often ineffective and do not treat the underlying pathology. Rodent bladder-injury models that induce some of the symptoms observed in IC/PBS have been used to evaluate potential treatments for IC/PBS [4-9]. One injury model, bacterial cystitis (urinary tract infection, UTI) is known to cause a similar constellation of symptoms as observed in IC/PBS (i.e. urinary frequency and urgency [10-12]). In addition, bacterial cystitis can be modeled in rodents through bladder exposure to uropathogenic Escherichia Coli (UPEC) [13,14]. Bladder infections due to UPEC are responsible for approximately 80% of UTIs in otherwise healthy women [15,16]. Understanding the underlying molecular mechanisms of both non-inflammatory bladder pain and inflammatory bladder pain due to UPEC infection could lead to the development of novel treatments for painful bladder infections as well as for IC/PBS and po
Genomic structure of metabotropic glutamate receptor 7 and comparison of genomic structures of extracellular domains of mGluR family
Qingfa Wu,Wei Dong,Xiaohua Qi,Weidong Bao,Yuxin Niu,Yiling Zhang,Haiqing Zhang,Chong Chen,Bin Liu,Songnian Hu,Jian Wang,Huanming Yang
Chinese Science Bulletin , 2002, DOI: 10.1360/02tb9295
Abstract: Metabotropic glutamate receptor 7, coupled with a chemical neurotransmitter L-glutamate, plays an important role in the development of many psychiatric and neurological disorders. To study the biological and genetic mechanism of the mGluR7-related diseases, a physical map covering the full-length mGluR7 genomic sequence has been constructed through seed clone screening and fingerprinting database searching. These BAC clones in the physical map have been sequenced with shotgun strategy and assembled by Phred-Phrap-Consed software; the error rate of the final genomic sequence is less than 0.01%. mGluR7 spans 880 kb genomic region, the GC content and repeat content of mGluR7 genomic sequence are 38% and 37.5% respectively. mGluR7 has a typical “house-keeping” promoter and consists of 11 exons, with introns ranging from 6 kb to 285 kb. mGhiR7a and mGluR7b are two known alternatively splicing variants. Comparing the genomic structures of extracellular domains of mGluR family, their genomic structures can be subdivided into three groups, which are consistent with that of proteins. Although the genomic organization of mGluR7’s group is conserved, the majority of introns in the extracellular segments vary dramatically. It is an obvious trend of the increasing intron size inverse proportion to phylogenetic time. Variation of genomic structure is higher than that of protein, which is attributed to the species characteristic regulation of gene expression.
Activity Modes in Thalamocortical Relay Neurons are Modulated by Gq/G11 Family G-proteins – Serotonergic and Glutamatergic Signaling
Philippe Coulon,Tatyana Kanyshkova,Tilman Broicher,Thomas Munsch,Nina Wettschureck,Thomas Seidenbecher,Sven G. Meuth,Stefan Offermanns,Hans-Christian Pape,Thomas Budde
Frontiers in Cellular Neuroscience , 2010, DOI: 10.3389/fncel.2010.00132
Abstract: In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Gαq knockout on the background of a constitutive Gα11 knockout (Gαq/Gα11?/?) was used to determine the contribution of Gq/G11 family G-proteins to metabotropic serotonin (5-HT) and glutamate (Glu) function in the dorsal part of the lateral geniculate nucleus (dLGN). In control mice, current clamp recordings showed that α-m-5-HT induced a depolarization of Vrest which was sufficient to suppress burst firing. This depolarization was concentration-dependent (100 μM: +6 ± 1 mV, n = 10; 200 μM: +10 ± 1 mV, n = 7) and had a conditioning effect on the activation of other Gαq-mediated pathways. The depolarization was significantly reduced in Gαq/Gα11?/? (100 μM: 3 ± 1 mV, n = 11; 200 μM: 5 ± 1 mV, n = 6) and was apparently insufficient to suppress burst firing. Activating Gαq-coupled muscarinic receptors affected the magnitude of α-m-5-HT-induced effects in a reciprocal manner. Furthermore, the depolarizing effect of mGluR1 agonists was significantly reduced in Gαq/Gα11?/? mice. Immunohistochemical stainings revealed binding of 5-HT2CR- and mGluR1α-, but not of 5-HT2AR-specific antibodies in the dLGN of Gαq/Gα11?/? mice. In conclusion, these findings demonstrate that transmitters of ascending brainstem fibers and corticofugal fibers both signal via a central element in the form of Gq/G11-mediated pathways to control activity modes in the TC system.
Positive Allosteric Modulators of Type 5 Metabotropic Glutamate Receptors (mGluR5) and Their Therapeutic Potential for the Treatment of CNS Disorders
Richard M. Cleva,M. Foster Olive
Molecules , 2011, DOI: 10.3390/molecules16032097
Abstract: Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury
Kimberly R Byrnes, David J Loane, Bogdan A Stoica, Jiangyang Zhang, Alan I Faden
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-43
Abstract: One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.Traumatic brain injury (TBI) causes cell death and neurological dysfunction through both direct physical disruption of tissue or pathways (primary injury), as well as delayed and potentially reversible molecular and cellular pathophysiological mechanisms (secondary injury) resulting in progressive white matter and grey matter damage [1]. Such delayed injury begins within seconds to minutes after the insult and may continue for days, weeks or potentially months to years [2]. These processes are characterized by neuronal cell death, as well as infiltration and activation of blood-borne immune cells, such as macrophages and lymphocytes, and activation of resident microglia [3].After TBI, microglia become activated and undergo marked changes in cell morphology and behavior. Upon acti
Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate levels and neurocognition in non-smoking, active alcoholics
Xia Yan,Ma Dongying,Hu Jian,Tang Chunling
Behavioral and Brain Functions , 2012, DOI: 10.1186/1744-9081-8-42
Abstract: Background We studied the effects of single nucleotide polymorphisms (SNPs) in the metabotropic glutamate receptor 3 (GRM3) gene on brain N-acetylaspartate (NAA) concentrations and executive function (EF) skills in non-smoking, active alcoholics, and evaluated associations between these variables. Methods SNPs (rs6465084, rs1468412, and rs2299225) in GRM3 were genotyped in 49 male, non-smoking, alcohol-dependent patients and 45 healthy control subjects using ligase detection reactions. NAA/creatine (Cr) ratios in left prefrontal gray matter (GM) and white matter (WM), left parietal GM, left parietal WM, and cerebellar vermis regions were measured by Proton 1 H Magnetic resonance spectroscopy (MRS). EF was measured by the Wisconsin Card Sorting Test (WCST). Results Compared to controls, alcoholics had lower NAA/Cr ratios in prefrontal GM and WM regions and performed more poorly on all EF tests (P < 0.001). Alcoholics with the A/A genotype for SNP rs6465084 had lower NAA/Cr ratios in prefrontal GM and WM regions and had poorer EF skills than alcoholics who were G-carriers for this SNP (P < 0.01). Non-alcoholics with the A/A genotype for rs6465084 also had lower NAA/Cr levels in prefrontal GM and made more random errors in the WCST than G-carriers (P < 0.01). The A/A genotype group for SNP rs6465084 was significantly different from the G carriers for the variables of NAA/Cr ratios and WCST scores in both alcoholics and controls (P < 0.05). Alcoholics who were T-carriers for rs1468412 had lower NAA/Cr ratios in prefrontal GM and showed poorer EF skills (P < 0.05). No effects of rs2299225 genotype on NAA/Cr or executive skills were observed. NAA/Cr in left prefrontal regions correlated with certain parameters of EF testing in both alcoholics and controls (P < 0.05), but the significance of this correlation among alcoholics disappeared after adjustment for the effects of genotype. Conclusions Our results provide evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in alcohol dependence. It is possible that certain GRM3 SNP genotypes (the A/A genotype of rs6465084 and the T allele of rs1468412) may further lower NAA/Cr levels and EF skills in addition to the effect of alcohol.
(S)- 3,5-Dihydroxyphenylglycine )an agonist for group I metabotropic glutamate receptors( induced synaptic potentiation at excitatory synapses on fast spiking GABAergic cells in visual cortex
Abdolrahman Sarihi,Alireza Komaki,Tadaharu Tsumoto
Physiology and Pharmacology , 2008,
Abstract: Introduction: (S)- 3,5-Dihydroxyphenylglycine (DHPG) is an agonist for group I metabotropic glutamate receptors. DHPG-induced synaptic depression of excitatory synapses on hippocampal pyramidal neurons is well known model for synaptic plasticity studies. The aim of the present study was to examine the effects of DHPG superfusion on excitatory synapses on pyramidal and fast-spiking GABAergic cells (FS-GABA) of layer II/III of mice visual cortex. Methods: Effects of DHPG was examined in visual cortical slices of GAD67-GFP knock-in mice using whole-cell recordings of excitatory postsynaptic potentials (EPSPs) in layer II/III cells evoked by layer IV stimulation. In part of experiments, long term potentiation (LTP) was induced by theta burst stimulation (TBS) paired with postsynaptic depolarization. Results: DHPG induced potentiation of EPSPs of FS-GABA neurons in dose- and use-dependent manners but it has no effect on pyramidal cell excitatory synapses. An antagonist for type 5 metabotropic glutamate receptors (mGluR5) blocked DHPG-induced LTP, while an antagonist for mGluR1 was not effective. This potentiation and TBS-induced LTP occluded each other. Conclusion: Based on important role of FS-GABA cells in cortical neuronal circuit, mGlur5-dependent LTP may play a role in, enhancement or maintenance of synchronized activity of cortical pyramidal neurons.
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