Journal articles: 'MGlu2 receptor'

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Bruno, Valeria, Giuseppe Battaglia, Agata Copani, Mara D'Onofrio, P. Di Iorio, Antonio De Blasi, Daniela Melchiorri, Peter J. Flor, and Ferdinando Nicoletti. "Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs." Journal of Cerebral Blood Flow & Metabolism 21, no. 9 (September 2001): 1013–33. http://dx.doi.org/10.1097/00004647-200109000-00001.

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Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not “mediate,” but rather “modulate” excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.

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Chaki, Shigeyuki, Hiroyuki Koike, and Kenichi Fukumoto. "Targeting of Metabotropic Glutamate Receptors for the Development of Novel Antidepressants." Chronic Stress 3 (January 2019): 247054701983771. http://dx.doi.org/10.1177/2470547019837712.

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Since discovering that ketamine has robust antidepressant effects, the glutamatergic system has been proposed as an attractive target for the development of novel antidepressants. Among the glutamatergic system, metabotropic glutamate (mGlu) receptors are of interest because mGlu receptors play modulatory roles in glutamatergic transmission, consequently, agents acting on mGlu receptors might not exert the adverse effects associated with ketamine. mGlu receptors have eight subtypes that are classified into three groups, and the roles of each mGlu receptor subtype in depression are being investigated. To date, the potential use of mGlu5 receptor antagonists and mGlu2/3 receptor antagonists as antidepressants has been actively investigated, and the mechanisms underlying these antidepressant effects are being delineated. Although the outcomes of clinical trials using an mGlu5 receptor negative allosteric modulator and an mGlu2/3 receptor negative allosteric modulator have not been encouraging, these trials have been inconclusive, and additional trials using other compounds with more appropriate profiles are needed. In contrast, the roles of group III mGlu receptors have not yet been fully elucidated because of a lack of suitable pharmacological tools. Nonetheless, investigations of the use of mGlu4 and mGlu7 receptors as drug targets for the development of antidepressants have been ongoing, and some interesting evidence has been obtained.

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Hagena, Hardy, and Denise Manahan-Vaughan. "Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience." Cells 11, no. 21 (October 24, 2022): 3352. http://dx.doi.org/10.3390/cells11213352.

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The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (> 24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.

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Johnson, M. P., E. S. Nisenbaum, T. H. Large, R. Emkey, M. Baez, and A. E. Kingston. "Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists." Biochemical Society Transactions 32, no. 5 (October 26, 2004): 881–87. http://dx.doi.org/10.1042/bst0320881.

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Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

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Xiang, Zixiu, Xiaohui Lv, Xin Lin, Daniel E. O’Brien, Molly K. Altman, Craig W. Lindsley, Jonathan A. Javitch, Colleen M. Niswender, and P. Jeffrey Conn. "Input-specific regulation of glutamatergic synaptic transmission in the medial prefrontal cortex by mGlu2/mGlu4 receptor heterodimers." Science Signaling 14, no. 677 (April 6, 2021): eabd2319. http://dx.doi.org/10.1126/scisignal.abd2319.

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Metabotropic glutamate receptors (mGluRs) are G protein–coupled receptors that regulate various aspects of central nervous system processing in normal physiology and in disease. They are thought to function as disulfide-linked homodimers, but studies have suggested that mGluRs can form functional heterodimers in cell lines. Using selective allosteric ligands, ex vivo brain slice electrophysiology, and optogenetic approaches, we found that two mGluR subtypes—mGluR2 and mGluR4 (or mGlu2 and mGlu4)—exist as functional heterodimers that regulate excitatory transmission in a synapse-specific manner within the rodent medial prefrontal cortex (mPFC). Activation of mGlu2/mGlu4 heterodimers inhibited glutamatergic signaling at thalamo-mPFC synapses but not at hippocampus-mPFC or amygdala-mPFC synapses. These findings raise the possibility that selectively targeting these heterodimers could be a therapeutic strategy for some neurologic and neuropsychiatric disorders involving specific brain circuits.

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Storto, M., M. Sallese, L. Salvatore, R. Poulet, DF Condorelli, P. Dell'Albani, MF Marcello, et al. "Expression of metabotropic glutamate receptors in the rat and human testis." Journal of Endocrinology 170, no. 1 (July 1, 2001): 71–78. http://dx.doi.org/10.1677/joe.0.1700071.

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The G protein-coupled receptor kinase type 4 mediates the homologous desensitisation of type-1 metabotropic glutamate (mGlu1) receptors and is predominantly expressed in the testis. Hence, we searched for the expression of mGlu1 or other mGlu receptor subtypes in rat and human testes. RT-PCR analysis showed the presence of mGlu1, -4 and -5 (but not -2 or -3) receptor mRNA in the rat testis. The presence of mGlu1 and -5 (but not mGlu2/3) receptor proteins was also demonstrated by Western blot analysis. In the rat testis, both mGlu1a and -5 receptors were highly expressed in cells of the germinal line. It is likely that these receptors are functional, because the agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, was able to stimulate inositol phospholipid hydrolysis in slices prepared from rat testes. Immunocytochemical analysis of bioptic samples from human testes showed a high expression of mGlu5 receptors inside the seminiferous tubuli, whereas mGlu1a immunoreactivity was restricted to intertubular spaces. mGlu5 receptors were also present in mature spermatozoa, where they were localised in the mid-piece and tail. This localisation coincided with that of beta-arrestin, a protein that is critically involved in the homologous desensitisation and internalisation of G protein-coupled receptors. Taken collectively, these results offer the first evidence for the expression of any glutamate receptor in testes, and suggest that at least mGlu5 receptors are present and functionally active in mature human sperm.

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Marciniak, Marcin, Barbara Chruścicka, Tomasz Lech, Grzegorz Burnat, and Andrzej Pilc. "Expression of group III metabotropic glutamate receptors in the reproductive system of male mice." Reproduction, Fertility and Development 28, no. 3 (2016): 369. http://dx.doi.org/10.1071/rd14132.

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Although the presence of metabotropic glutamate (mGlu) receptors in the central nervous system is well documented, they have recently been found in peripheral and non-neuronal tissues. In the present study we investigated the expression of group III mGlu receptors in the reproductive system of male mice. Reverse transcription–polymerase chain reaction analysis revealed the presence of mGlu6, mGlu7 and mGlu8 (but not mGlu4) receptor transcripts in testes and epididymides from adult mice. In addition, expression of mGlu6 (Grm6) and mGlu8 receptor (Grm8) mRNA was detected in spermatozoa isolated from the vas deferens. The vas deferens was found to contain only mGlu7 receptor (Grm7) mRNA, which was particularly intense in 21-day-old male mice. In penile homogenates, only the mGlu7 receptor signal was detected. Genetic ablation of the mGlu7 receptor in males led to fertility disorders manifested by decreased insemination capability as well as deterioration of sperm parameters, particularly sperm motility, vitality, sperm membrane integrity and morphology, with a simultaneous increase in sperm concentration. These results indicate that constitutively expressed mGlu receptors in the male reproductive system may play an important role in ejaculation and/or erection processes, as well as in the formation and maturation of spermatozoa.

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Hofmann, Christopher S., Sheridan Carrington, Andrew N. Keller, Karen J. Gregory, and Colleen M. Niswender. "Regulation and functional consequences of mGlu4 RNA editing." RNA 27, no. 10 (July 8, 2021): 1220–40. http://dx.doi.org/10.1261/rna.078729.121.

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Metabotropic glutamate receptor 4 (mGlu4) is one of eight mGlu receptors within the Class C G protein-coupled receptor superfamily. mGlu4 is primarily localized to the presynaptic membrane of neurons where it functions as an auto and heteroreceptor controlling synaptic release of neurotransmitter. mGlu4 is implicated in numerous disorders and is a promising drug target; however, more remains to be understood about its regulation and pharmacology. Using high-throughput sequencing, we have validated and quantified an adenosine-to-inosine (A-to-I) RNA editing event that converts glutamine 124 to arginine in mGlu4; additionally, we have identified a rare but novel K129R site. Using an in vitro editing assay, we then validated the pre-mRNA duplex that allows for editing by ADAR enzymes and predicted its conservation across the mammalian species. Structural modeling of the mGlu4 protein predicts the Q124R substitution to occur in the B helix of the receptor that is critical for receptor dimerization and activation. Interestingly, editing of a receptor homodimer does not disrupt G protein activation in response to the endogenous agonist, glutamate. Using an assay designed to specifically measure heterodimer populations at the surface, however, we found that Q124R substitution decreased the propensity of mGlu4 to heterodimerize with mGlu2 and mGlu7. Our study is the first to extensively describe the extent and regulatory factors of RNA editing of mGlu4 mRNA transcripts. In addition, we have proposed a novel functional consequence of this editing event that provides insights regarding its effects in vivo and expands the regulatory capacity for mGlu receptors.

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Haubrich, Jordi, Joan Font, Robert B. Quast, Anne Goupil-Lamy, Pauline Scholler, Damien Nevoltris, Francine Acher, et al. "A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers." Proceedings of the National Academy of Sciences 118, no. 33 (August 12, 2021): e2105848118. http://dx.doi.org/10.1073/pnas.2105848118.

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There is growing interest in developing biologics due to their high target selectivity. The G protein–coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.

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Zammataro, Magda, Santina Chiechio, Michael C. Montana, Anna Traficante, Agata Copani, Ferdinando Nicoletti, and Robert W. Gereau. "mGlu2 Metabotropic Glutamate Receptors Restrain Inflammatory Pain and Mediate the Analgesic Activity of Dual mGlu2/mGlu3 Receptor Agonists." Molecular Pain 7 (January 2011): 1744–8069. http://dx.doi.org/10.1186/1744-8069-7-6.

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Schoepp, Darryle D., James A. Monn, Gerard J. Marek, George A. Ghajanian, and Bita Moghaddam. "LY3 54740: A Systemically Active mGlu2/mGlu3 Receptor Agonist." CNS Drug Reviews 5, no. 1 (June 7, 2006): 1–12. http://dx.doi.org/10.1111/j.1527-3458.1999.tb00082.x.

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Taddeucci, Alice, Guendalina Olivero, Alessandra Roggeri, Claudio Milanese, Francesco Paolo Di Giorgio, Massimo Grilli, Mario Marchi, Beatrice Garrone, and Anna Pittaluga. "Presynaptic 5-HT2A-mGlu2/3 Receptor–Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis." Cells 11, no. 19 (September 28, 2022): 3035. http://dx.doi.org/10.3390/cells11193035.

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The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 μM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 μM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1–10 μM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 μM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.

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Chaki, Shigeyuki, and Kenichi Fukumoto. "Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine." International Journal of Molecular Sciences 20, no. 6 (March 13, 2019): 1270. http://dx.doi.org/10.3390/ijms20061270.

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Numerous studies have demonstrated the antidepressant effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists in various rodent models. Importantly, it has been shown that the antidepressant effects of mGlu2/3 receptor antagonists in rodent models are similar to those of ketamine, which exerts rapid and long-lasting antidepressant effects in patients with major depressive disorders, including patients with treatment-resistant depression. In addition, the synaptic mechanisms underlying the effects of mGlu2/3 receptor antagonists are reported to be similar to those underlying the effects of ketamine. The roles of the serotonergic system in the antidepressant effects of mGlu2/3 receptor antagonists have recently been demonstrated. Moreover, it was investigated how mGlu2/3 receptor antagonists interact with the serotonergic system to exert antidepressant effects. Notably, the same neural mechanisms as those underlying the effects of ketamine may be involved in the antidepressant actions of the mGlu2/3 receptor antagonists. In this review, we shall summarize the antidepressant potential of mGlu2/3 receptor antagonists and their mechanisms of action in comparison with those of ketamine. In particular, we shall focus on the roles of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists.

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Jourdain, Vincent A., Nicolas Morin, Laurent Grégoire, Marc Morissette, and Thérèse Di Paolo. "Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy." Journal of Neurosurgery 123, no. 6 (December 2015): 1383–93. http://dx.doi.org/10.3171/2014.10.jns141570.

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OBJECT Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. METHODS The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys. RESULTS The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor–specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor–specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. CONCLUSIONS These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control.

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Homayoun, Houman, Mark E. Jackson, and Bita Moghaddam. "Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats." Journal of Neurophysiology 93, no. 4 (April 2005): 1989–2001. http://dx.doi.org/10.1152/jn.00875.2004.

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Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)–dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.

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Cieślik, Paulina, Adrianna Radulska, Iwona Pelikant-Małecka, Agata Płoska, Leszek Kalinowski, and Joanna M. Wierońska. "Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice." International Journal of Molecular Sciences 20, no. 11 (June 6, 2019): 2781. http://dx.doi.org/10.3390/ijms20112781.

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Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25−0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug–drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.

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Linden, Anni-Maija, Melvin Baez, Marcelle Bergeron, and Darryle D. Schoepp. "Effects of mGlu2 or mGlu3 receptor deletions on mGlu2/3 receptor agonist (LY354740)-induced brain c-Fos expression: Specific roles for mGlu2 in the amygdala and subcortical nuclei, and mGlu3 in the hippocampus." Neuropharmacology 51, no. 2 (August 2006): 213–28. http://dx.doi.org/10.1016/j.neuropharm.2006.03.014.

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Chen, Wei-Ping, and Annette L. Kirchgessner. "Activation of group II mGlu receptors inhibits voltage-gated Ca2+ currents in myenteric neurons." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 6 (December 1, 2002): G1282—G1289. http://dx.doi.org/10.1152/ajpgi.00216.2002.

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The enteric nervous system (ENS) contains functional ionotropic and group I metabotropic glutamate (mGlu) receptors. In this study, we determined whether enteric neurons express group II mGlu receptors and the effects of mGlu receptor activation on voltage-gated Ca2+ currents in these cells. (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a group II mGlu receptor agonist, reversibly suppressed the Ba2+current in myenteric neurons isolated from the guinea pig ileum. Significant inhibition was also produced by l-glutamate and the group II mGlu receptor agonists, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) and (2S,1′S,2′S)-2-(2-carboxycyclopropyl)glycine (l-CCG-I), with a rank order potency of 2R,4R-APDC > DCG-IV >l-glutamate > l-CCG-I, and was reduced by the group II mGlu receptor antagonist LY-341495. Pretreatment of neurons with pertussis toxin (PTX) reduced the action of mGlu receptor agonists, suggesting participation of Gi/Goproteins. Finally, ω-conotoxin GVIA blocked current suppression by DCG-IV, suggesting modulation of N-type calcium channels. mGlu2/3 receptor immunoreactivity was displayed by neurons in culture and in the submucosal and myenteric plexus of the ileum. A subset of these cells displayed a glutamatergic phenotype as shown by the expression of vesicular glutamate transporter 2. These results provide the first evidence for functional group II mGlu receptors in the ENS and show that these receptors are PTX sensitive and negatively coupled to N-type calcium channels. Inhibition of N-type calcium channels produced by activation of group II mGlu receptors may modulate enteric neurotransmission.

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Menezes, M. M., M. A. Santini, M. J. Benvenga, G. J. Marek, K. M. Merchant, J. D. Mikkelsen, and K. A. Svensson. "The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex." Neuroscience Journal 2013 (November 19, 2013): 1–8. http://dx.doi.org/10.1155/2013/736439.

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Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30 mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10 mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor (5-HT2AR)-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.

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Joffe, Max E., and P. Jeffrey Conn. "Antidepressant potential of metabotropic glutamate receptor mGlu2 and mGlu3 negative allosteric modulators." Neuropsychopharmacology 44, no. 1 (September 10, 2018): 214–36. http://dx.doi.org/10.1038/s41386-018-0192-8.

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Zanos, Panos, Jaclyn N. Highland, Brent W. Stewart, Polymnia Georgiou, Carleigh E. Jenne, Jacqueline Lovett, Patrick J. Morris, et al. "(2R,6R)-hydroxynorketamine exerts mGlu2receptor-dependent antidepressant actions." Proceedings of the National Academy of Sciences 116, no. 13 (March 13, 2019): 6441–50. http://dx.doi.org/10.1073/pnas.1819540116.

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Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu2/3receptor agonist (LY379268)-induced body temperature increases in mice lacking theGrm3, but notGrm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu2/3receptor agonist and absent in mice lacking theGrm2, but notGrm3−/−, gene. Combined subeffective doses of the mGlu2/3receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu2receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu2receptor function in clinical trials for treatment-resistant depression either alone or in combination.

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Murat, Samy, Mathilde Bigot, Jonathan Chapron, Gabriele M. König, Evi Kostenis, Giuseppe Battaglia, Ferdinando Nicoletti, et al. "5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling." Molecular Psychiatry 24, no. 11 (June 1, 2018): 1610–26. http://dx.doi.org/10.1038/s41380-018-0069-6.

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Homayoun, Houman, and Bita Moghaddam. "Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs." Proceedings of the National Academy of Sciences 105, no. 46 (November 12, 2008): 18041–46. http://dx.doi.org/10.1073/pnas.0806669105.

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Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.

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Wischhof, Lena, and Michael Koch. "5-HT2A and mGlu2/3 receptor interactions." Behavioural Pharmacology 27, no. 1 (February 2016): 1–11. http://dx.doi.org/10.1097/fbp.0000000000000183.

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Chaki, Shigeyuki. "mGlu2/3 Receptor Antagonists as Novel Antidepressants." Trends in Pharmacological Sciences 38, no. 6 (June 2017): 569–80. http://dx.doi.org/10.1016/j.tips.2017.03.008.

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Lane, Tracy A., Thomas Boerner, David M. Bannerman, James NC Kew, Elizabeth M. Tunbridge, Trevor Sharp, and Paul J. Harrison. "Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice." BMC Neuroscience 14, no. 1 (2013): 102. http://dx.doi.org/10.1186/1471-2202-14-102.

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Leembruggen, Anita J. L., Yuqing Lu, Haozhe Wang, Volkan Uzungil, Thibault Renoir, Anthony J. Hannan, Lincon A. Stamp, Marlene M. Hao, and Joel C. Bornstein. "Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon." Biomolecules 13, no. 1 (January 9, 2023): 139. http://dx.doi.org/10.3390/biom13010139.

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Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function.

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Kaczorowska, Katarzyna, Anna Stankiewicz, Ryszard Bugno, Maria H. Paluchowska, Grzegorz Burnat, Piotr Brański, Paulina Cieślik, et al. "Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu7 Receptor Modulation Activity and Antipsychotic-Like Properties." International Journal of Molecular Sciences 24, no. 3 (January 19, 2023): 1981. http://dx.doi.org/10.3390/ijms24031981.

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Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.

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Rafało-Ulińska, Anna, Piotr Brański, and Agnieszka Pałucha-Poniewiera. "Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism." Pharmaceuticals 15, no. 2 (January 21, 2022): 125. http://dx.doi.org/10.3390/ph15020125.

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Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

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KANIA, BOGDAN FELIKS, URSZULA BRACHA, GRZEGORZ LONC, and TOMASZ WOJNAR. "Significance of metabotropic glutamate receptor antagonists in experimental neuropathic pain in animals." Medycyna Weterynaryjna 76, no. 10 (2020): 6460–2020. http://dx.doi.org/10.21521/mw.6460.

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Neuropathic pain is a serious therapeutic problem. Current therapy is often ineffective, and the available drugs have serious side effects. For these reasons, the search for alternative therapeutic solutions is underway. Recent research on metabotropic receptors for glutamic acid (mGluR) gives great hope for the development of a new type of drug in the treatment of neuropathic pain. Particularly promising are antagonists of mGluR group I receptors. There are many studies demonstrating the efficacy of non-competitive mGlu1 and mGlu5 receptor antagonists in animal models of neuropathic pain. The purpose of this study was to gather information obtained from research on the role of mGluR antagonists in neuropathic pain. The blockade of intracellular glutamatergic receptor could represent a new strategy for the development of effective therapies for neuropathic pain.

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Pinkerton, Anthony B., Rowena V. Cube, John H. Hutchinson, Joyce K. James, Michael F. Gardner, Hervé Schaffhauser, Blake A. Rowe, Lorrie P. Daggett, and Jean-Michel Vernier. "Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-Thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators." Bioorganic & Medicinal Chemistry Letters 14, no. 23 (December 2004): 5867–72. http://dx.doi.org/10.1016/j.bmcl.2004.09.028.

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Pinkerton, Anthony B., Rowena V. Cube, John H. Hutchinson, Joyce K. James, Michael F. Gardner, Blake A. Rowe, Hervé Schaffhauser, et al. "Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators." Bioorganic & Medicinal Chemistry Letters 15, no. 6 (March 2005): 1565–71. http://dx.doi.org/10.1016/j.bmcl.2005.01.077.

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Woolley, M. L., D. J. Pemberton, S. Bate, C. Corti, and D. N. C. Jones. "The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity." Psychopharmacology 196, no. 3 (December 5, 2007): 431–40. http://dx.doi.org/10.1007/s00213-007-0974-x.

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Murat, S., M. Bigot, P. Rondard, E. Bourinet, G. Battaglia, F. Nicoletti, J. Bockaert, P. Marin, and F. Vandermoere. "Serotonin 5-HT2A receptor-dependent phosphorylation of glutamate mGLU2 at Ser843 promotes mGLU2-operated Gi/o signaling." European Neuropsychopharmacology 27 (March 2017): S5—S6. http://dx.doi.org/10.1016/s0924-977x(17)30072-x.

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O’Brien, Daniel E., Douglas M. Shaw, Hyekyung P. Cho, Alan J. Cross, Steven S. Wesolowski, Andrew S. Felts, Jonas Bergare, et al. "Differential Pharmacology and Binding of mGlu2 Receptor Allosteric Modulators." Molecular Pharmacology 93, no. 5 (March 15, 2018): 526–40. http://dx.doi.org/10.1124/mol.117.110114.

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Copeland, C. S., T. M. Wall, R. E. Sims, S. A. Neale, E. Nisenbaum, H. R. Parri, and T. E. Salt. "Astrocytes modulate thalamic sensory processing via mGlu2 receptor activation." Neuropharmacology 121 (July 2017): 100–110. http://dx.doi.org/10.1016/j.neuropharm.2017.04.019.

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Tresadern, Gary, José-Maria Cid, and Andrés A. Trabanco. "QSAR design of triazolopyridine mGlu2 receptor positive allosteric modulators." Journal of Molecular Graphics and Modelling 53 (September 2014): 82–91. http://dx.doi.org/10.1016/j.jmgm.2014.07.006.

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Svensson, Kjell. "THE MGLU2 RECEPTOR AS A NOVEL DRUG TARGET FOR SCHIZOPHRENIA." Schizophrenia Research 117, no. 2-3 (April 2010): 114. http://dx.doi.org/10.1016/j.schres.2010.02.037.

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Megens, Anton A. H. P., Herman M. R. Hendrickx, Koen A. Hens, Willem J. P. E. Talloen, and Hilde Lavreysen. "mGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats." European Journal of Pharmacology 727 (March 2014): 130–39. http://dx.doi.org/10.1016/j.ejphar.2014.01.044.

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HERMANS, Emmanuel, and R. A. John CHALLISS. "Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors." Biochemical Journal 359, no. 3 (October 25, 2001): 465–84. http://dx.doi.org/10.1042/bj3590465.

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In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABAB receptor (where GABA is γ-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders.

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Bushell, Trevor J., Gilles Sansig, Valerie J. Collett, Herman van der Putten, and Graham L. Collingridge. "Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7." Scientific World JOURNAL 2 (2002): 730–37. http://dx.doi.org/10.1100/tsw.2002.146.

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Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

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Schlumberger, Chantal, Małgorzata Pietraszek, Andreas Gravius, Kai-Uwe Klein, Sergio Greco, Lorenzo Morè, and Wojciech Danysz. "Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity." European Journal of Pharmacology 623, no. 1-3 (November 2009): 73–83. http://dx.doi.org/10.1016/j.ejphar.2009.09.006.

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Vales, Karel, Jan Svoboda, Kristina Benkovicova, Vera Bubenikova-Valesova, and Ales Stuchlik. "The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801." European Journal of Pharmacology 639, no. 1-3 (August 2010): 91–98. http://dx.doi.org/10.1016/j.ejphar.2009.11.067.

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Tong, Qingchun, Raogo Ouedraogo, and Annette L. Kirchgessner. "Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets." American Journal of Physiology-Endocrinology and Metabolism 282, no. 6 (June 1, 2002): E1324—E1333. http://dx.doi.org/10.1152/ajpendo.00460.2001.

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Pancreatic islets contain ionotropic glutamate receptors that can modulate hormone secretion. The purpose of this study was to determine whether islets express functional group III metabotropic glutamate (mGlu) receptors. RT-PCR analysis showed that rat islets express the mGlu8 receptor subtype. mGlu8 receptor immunoreactivity was primarily displayed by glucagon-secreting α-cells and intrapancreatic neurons. By demonstrating the immunoreactivities of both glutamate and the vesicular glutamate transporter 2 (VGLUT2) in these cells, we established that α-cells express a glutamatergic phenotype. VGLUT2 was concentrated in the secretory granules of islet cells, suggesting that glutamate might play a role in the regulation of glucagon processing. The expression of mGlu8 by glutamatergic cells also suggests that mGlu8 may function as an autoreceptor to regulate glutamate release. Pancreatic group III mGlu receptors are functional because mGlu8 receptor agonists inhibited glucagon release and forskolin-induced accumulation of cAMP in isolated islets, and (R,S)-cyclopropyl-4-phosphonophenylglycine, a group III mGlu receptor antagonist, reduced these effects. Because excess glucagon secretion causes postprandial hyperglycemia in patients with type 2 diabetes, group III mGlu receptor agonists could be of value in the treatment of these patients.

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Schoepp, Darryle, and Gerard Marek. "Preclinical Pharmacology of mGlu2 / 3 Receptor Agonists: Novel Agents for Schizophrenia?" Current Drug Target -CNS & Neurological Disorders 1, no. 2 (April 1, 2002): 215–25. http://dx.doi.org/10.2174/1568007024606177.

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Magnus, Nicholas A., D. Scott Coffey, Amy C. DeBaillie, Chauncey D. Jones, Iwona A. Kaluzna, Spiros Kambourakis, Yangwei J. Pu, Lin Wang, and James P. Wepsiec. "Diarylketone Ketoreductase Screen and Synthesis Demonstration to Access mGlu2 Receptor Potentiators." Organic Process Research & Development 15, no. 6 (November 18, 2011): 1377–81. http://dx.doi.org/10.1021/op2002479.

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Zhang, Yue, Xiaohong Zhu, Honghui Zhang, Junfang Yan, Peiyi Xu, Peng Wu, Song Wu, and Chen Bai. "Mechanism Study of Proteins under Membrane Environment." Membranes 12, no. 7 (July 7, 2022): 694. http://dx.doi.org/10.3390/membranes12070694.

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Membrane proteins play crucial roles in various physiological processes, including molecule transport across membranes, cell communication, and signal transduction. Approximately 60% of known drug targets are membrane proteins. There is a significant need to deeply understand the working mechanism of membrane proteins in detail, which is a challenging work due to the lack of available membrane structures and their large spatial scale. Membrane proteins carry out vital physiological functions through conformational changes. In the current study, we utilized a coarse-grained (CG) model to investigate three representative membrane protein systems: the TMEM16A channel, the family C GPCRs mGlu2 receptor, and the P4-ATPase phospholipid transporter. We constructed the reaction pathway of conformational changes between the two-end structures. Energy profiles and energy barriers were calculated. These data could provide reasonable explanations for TMEM16A activation, the mGlu2 receptor activation process, and P4-ATPase phospholipid transport. Although they all belong to the members of membrane proteins, they behave differently in terms of energy. Our work investigated the working mechanism of membrane proteins and could give novel insights into other membrane protein systems of interest.

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Magnus, Nicholas A., Peter B. Anzeveno, D. Scott Coffey, David A. Hay, Michael E. Laurila, Jeffrey M. Schkeryantz, Bruce W. Shaw, and Michael A. Staszak. "Optimized Catalytic Enantioselective Aryl Transfer Process Gives Access to mGlu2 Receptor Potentiators." Organic Process Research & Development 11, no. 3 (May 2007): 560–67. http://dx.doi.org/10.1021/op0602268.

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Cartmell, Jayne, James A. Monn, and Darryle D. Schoepp. "The mGlu2/3 receptor agonist LY379268 selectively blocks amphetamine ambulations and rearing." European Journal of Pharmacology 400, no. 2-3 (July 2000): 221–24. http://dx.doi.org/10.1016/s0014-2999(00)00423-4.

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Tyler, Ryan E., Joyce Besheer, and Max E. Joffe. "Advances in translating mGlu2 and mGlu3 receptor selective allosteric modulators as breakthrough treatments for affective disorders and alcohol use disorder." Pharmacology Biochemistry and Behavior 219 (September 2022): 173450. http://dx.doi.org/10.1016/j.pbb.2022.173450.

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Journal articles on the topic 'MGlu2 receptor'

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