Artículos de revistas: "MGlu Receptors"

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Chaki, Shigeyuki, Hiroyuki Koike y Kenichi Fukumoto. "Targeting of Metabotropic Glutamate Receptors for the Development of Novel Antidepressants". Chronic Stress 3 (enero de 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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Bruno, Valeria, Giuseppe Battaglia, Agata Copani, Mara D'Onofrio, P. Di Iorio, Antonio De Blasi, Daniela Melchiorri, Peter J. Flor y Ferdinando Nicoletti. "Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs". Journal of Cerebral Blood Flow & Metabolism 21, n.º 9 (septiembre de 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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Marciniak, Marcin, Barbara Chruścicka, Tomasz Lech, Grzegorz Burnat y Andrzej Pilc. "Expression of group III metabotropic glutamate receptors in the reproductive system of male mice". Reproduction, Fertility and Development 28, n.º 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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Hagena, Hardy y Denise Manahan-Vaughan. "Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience". Cells 11, n.º 21 (24 de octubre de 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 y A. E. Kingston. "Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists". Biochemical Society Transactions 32, n.º 5 (26 de octubre de 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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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, n.º 1 (1 de julio de 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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Hofmann, Christopher S., Sheridan Carrington, Andrew N. Keller, Karen J. Gregory y Colleen M. Niswender. "Regulation and functional consequences of mGlu4 RNA editing". RNA 27, n.º 10 (8 de julio de 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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HERMANS, Emmanuel y 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, n.º 3 (25 de octubre de 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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Leembruggen, Anita J. L., Yuqing Lu, Haozhe Wang, Volkan Uzungil, Thibault Renoir, Anthony J. Hannan, Lincon A. Stamp, Marlene M. Hao y Joel C. Bornstein. "Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon". Biomolecules 13, n.º 1 (9 de enero de 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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Tong, Qingchun, Raogo Ouedraogo y Annette L. Kirchgessner. "Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets". American Journal of Physiology-Endocrinology and Metabolism 282, n.º 6 (1 de junio de 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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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, n.º 33 (12 de agosto de 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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Chen, Wei-Ping y 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, n.º 6 (1 de diciembre de 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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Ball, Lena, Julia Bauer y Dietmar Krautwurst. "Heterodimerization of Chemoreceptors TAS1R3 and mGlu2 in Human Blood Leukocytes". International Journal of Molecular Sciences 24, n.º 16 (18 de agosto de 2023): 12942. http://dx.doi.org/10.3390/ijms241612942.

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The expression of canonical chemosensory receptors of the tongue, such as the heteromeric sweet taste (TAS1R2/TAS1R3) and umami taste (TAS1R1/TAS1R3) receptors, has been demonstrated in many extra-oral cells and tissues. Gene expression studies have revealed transcripts for all TAS1 and metabotropic glutamate (mGlu) receptors in different types of immune cells, where they are involved, for example, in the chemotaxis of human neutrophils and the protection of T cells from activation-induced cell death. Like other class-C G protein-coupling receptors (GPCRs), TAS1Rs and mGlu receptors form heteromers within their families. Since mGlu receptors and TAS1R1/TAS1R3 share the same ligand, monosodium glutamate (MSG), we hypothesized their hitherto unknown heteromerization across receptor families in leukocytes. Here we show, by means of immunocytochemistry and co-IP/Western analysis, that across class-C GPCR families, mGlu2 and TAS1R3 co-localize and heterodimerize in blood leukocytes. Expressing the recombinant receptors in HEK-293 cells, we validated their heterodimerization by bioluminescence resonance energy transfer. We demonstrate MSG-induced, mGlu2/TAS1R3 heteromer-dependent gain-of-function and pertussis toxin-sensitive signaling in luminescence assays. Notably, we show that mGlu2/TAS1R3 is necessary and sufficient for MSG-induced facilitation of N-formyl-methionyl-leucyl-phenylalanine-stimulated IL-8 secretion in neutrophils, using receptor-specific antagonists. In summary, our results demonstrate mGlu2/TAS1R3 heterodimerization in leukocytes, suggesting cellular function-tailored chemoreceptor combinations to modulate cellular immune responses.

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Chung, Geehoon y Sang Jeong Kim. "Sustained Activity of Metabotropic Glutamate Receptor: Homer, Arrestin, and Beyond". Neural Plasticity 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/5125624.

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When activated, metabotropic glutamate receptors (mGlus) exert long-lasting changes within the glutamatergic synapses. One mechanism is a tonic effect of downstream signal transduction pathways via sustained activation of mGlu itself. Like many other G protein-coupled receptors (GPCRs), mGlu can exist in a constitutively active state, which persists agonist independently. In this paper, we review the current knowledge of the mechanisms underlying the constitutive activity of group I mGlus. The issues concerning Homer1a mechanism in the constitutive activity of group I mGlus and recent findings regarding the significant role ofβ-arrestin in sustained GPCR activity are also discussed. We propose that once in a state of sustained activation, the mGlu persistently activates downstream signaling pathways, including various adaptor proteins and kinases, such asβ-arrestin and mitogen-activated protein kinases. In turn, these effector molecules bind to or phosphorylate the mGlu C-terminal binding domains and consequently regulate the activation state of the mGlu.

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Mao, Li-Min, Alaya Bodepudi, Xiang-Ping Chu y John Q. Wang. "Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update". International Journal of Molecular Sciences 23, n.º 2 (13 de enero de 2022): 840. http://dx.doi.org/10.3390/ijms23020840.

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Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

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Bushell, Trevor J., Gilles Sansig, Valerie J. Collett, Herman van der Putten y 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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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, n.º 3 (19 de enero de 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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Olivero, Guendalina, Matteo Vergassola, Francesca Cisani, Alessandra Roggeri y Anna Pittaluga. "Presynaptic Release-regulating Metabotropic Glutamate Receptors: An Update". Current Neuropharmacology 18, n.º 7 (28 de julio de 2020): 655–72. http://dx.doi.org/10.2174/1570159x17666191127112339.

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: Metabotropic glutamate (mGlu) receptors represent the largest family of glutamate receptors in mammals and act as fine tuners of the chemical transmission in central nervous system (CNS). : In the last decade, results concerning the expression and the subcellular localization of mGlu receptors further clarified their role in physio-pathological conditions. Concomitantly, their pharmacological characterization largely improved thanks to the identification of new compounds (chemical ligands and antibodies recognizing epitopic sequences of the receptor proteins) that allowed to decipher the protein compositions of the naive receptors. : mGlu receptors are expressed at the presynaptic site of chemical synapses. Here, they modulate intraterminal enzymatic pathways controlling the migration and the fusion of vesicles to synaptic membranes as well as the phosphorylation of colocalized receptors. Both the control of transmitter exocytosis and the phosphorylation of colocalized receptors elicited by mGlu receptors are relevant events that dictate the plasticity of nerve terminals, and account for the main role of presynaptic mGlu receptors as modulators of neuronal signalling. : The role of the presynaptic mGlu receptors in the CNS has been the matter of several studies and this review aims at briefly summarizing the recent observations obtained with isolated nerve endings (we refer to as synaptosomes). We focus on the pharmacological characterization of these receptors and on their receptor-receptor interaction / oligo-dimerization in nerve endings that could be relevant to the development of new therapeutic approaches for the cure of central pathologies.

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Sato, Tomoaki, Koh-ichi Tanaka, Yoshiko Ohnishi, Masahiro Irifune y Takashige Nishikawa. "Effect of Donepezil on Group II mGlu Receptor Agonist- or Antagonist-Induced Amnesia on Passive Avoidance in Mice". Neural Plasticity 10, n.º 4 (2003): 319–25. http://dx.doi.org/10.1155/np.2003.319.

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We examined the effect of the acetylcholinesterase (ACHE) inhibitor, donepezil hydrocloride (DONP), on group II metabotropic glutamate (mGlu) receptor agonist- or antagonist-induced amnesia in the step-through passive avoidance task in male mice. DCG-IV, a group II mGlu receptor agonist, at dose of 50 ng and LY341495, a group II mGlu receptor antagonist, at dose of 300 ng, significantly attenuated the latency on the step-through task. The subcutaneous injection of DONP at dose of 1 mg/kg 1 hour before passive avoidance performance ameliorated the amnesia induced by DCG-IV and LY341495, whereas donepezil alone did not affect task latency. The results suggest that activation of group II mGlu receptors and disinhibition of the cAMP/PKA signaling pathway (caused by group II mGlu receptor antagonist) have a negative action on step-through passive avoidance memory performance, and that group II mGlu receptors and ACh interact to modulate learning and memory function.

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Chruścicka, Barbara, Grzegorz Burnat, Piotr Brański, Paulina Chorobik, Tomasz Lenda, Marcin Marciniak y Andrzej Pilc. "Tetracycline-Based System for Controlled Inducible Expression of Group III Metabotropic Glutamate Receptors". Journal of Biomolecular Screening 20, n.º 3 (13 de noviembre de 2014): 350–58. http://dx.doi.org/10.1177/1087057114559183.

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A stable and inducible expression of metabotropic glutamate receptor type 4, 7, and 8 was obtained in T-REx 293 cells using the tetracycline system. Tetracycline administration to the cell medium resulted in rapid induction and time-dependent expression of mGlu receptors, which also correlates with its functionality in a cAMP accumulation assay. The pharmacological properties of recombinant mGlu receptors were verified using orthosteric and allosteric ligands. Data suggest that the Tet-on inducible system is suitable for functional mGlu receptors’ expression and characterization by means of the cAMP accumulation assay. It makes this system a precise, reproducible, and large-scale screening method, as well as a reasonable tool to study signaling properties of mGlu receptors.

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Vázquez-Villa, Henar y Andrés A. Trabanco. "Progress toward allosteric ligands of metabotropic glutamate 7 (mGlu7) receptor: 2008–present". MedChemComm 10, n.º 2 (2019): 193–99. http://dx.doi.org/10.1039/c8md00524a.

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Gasparini, Fabrizio, Thérèse Di Paolo y Baltazar Gomez-Mancilla. "Metabotropic Glutamate Receptors for Parkinson's Disease Therapy". Parkinson's Disease 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/196028.

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Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson’s disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD.

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Hao, Junliang y Qi Chen. "Insights into the Structural Aspects of the mGlu Receptor Orthosteric Binding Site". Current Topics in Medicinal Chemistry 19, n.º 26 (10 de diciembre de 2019): 2421–46. http://dx.doi.org/10.2174/1568026619666191011094935.

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The amino terminal domain (ATD) of the metabotropic glutamate (mGlu) receptors contains the orthosteric glutamate recognition site, which is highly conserved across the eight mGlu receptor subtypes. In total, 29 X-ray crystal structures of the mGlu ATD proteins have been reported to date. These structures span across 3 subgroups and 6 subtypes, and include apo, agonist- and antagonist-bound structures. We will discuss the insights gained from the analysis of these structures with the focus on the interactions contributing to the observed group and subtype selectivity for select agonists. Furthermore, we will define the full expanded orthosteric ligand binding pocket (LBP) of the mGlu receptors, and discuss the macroscopic features of the mGlu ATD proteins.

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Bashkatova, Valentina G. y Sergey K. Sudakov. "Effects of metabotropic glutamate receptor antagonists on a rat model of maximum electroshock". I.P. Pavlov Russian Medical Biological Herald 29, n.º 2 (22 de julio de 2021): 193–200. http://dx.doi.org/10.17816/pavlovj43913.

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AIM: This study aimed to investigate the effect of metabotropic glutamate (mGlu) receptor antagonists on the development of seizure caused by maximum electric shock (MES) and the content of lipid peroxidation (LPO) products in the brain of rats. MATERIALS AND METHODS: Experiments were carried out on male Wistar rats (n = 87) with a mass of 180210 g. In this work, MES was administered. Selective antagonists of I and V subtype mGlu receptors were administered 1 h before MES was administered. Control rats were injected an equivalent amount of saline. The intensity of LPO processes was assessed in terms of the level of secondary products reacting with thiobarbituric acid via a spectrophotometric method. RESULTS: MES led to the development of pronounced clonictonic seizures and increased the level of LPO products in the cerebral cortex of rats by more than threefold. A selective antagonist of subtype V mGlu receptors almost completely stopped the tonic phase of rat seizures and largely prevented the intensification of LPO processes caused by MES. Tonic convulsions were observed in 44% of the experimental animals after the administration of a selective subtype I mGlu receptor antagonist. This antagonist also partially reduced the content of LPO products caused by the effect of MES. CONCLUSION: Thus, mGlu receptors are involved in the development of MES-induced seizures in rats. The most pronounced weakening of convulsive manifestations and the prevention of an increase in the level of LPO products caused by MES were observed in the block of subtype V mGlu receptors. The obtained data confirmed the possibility of using subtype V metabotropic receptor antagonists as anticonvulsants for the treatment of epilepsy with generalized convulsive seizures.

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Gasparini, F. y W. Spooren. "Allosteric Modulators for mGlu Receptors". Current Neuropharmacology 5, n.º 3 (1 de septiembre de 2007): 187–94. http://dx.doi.org/10.2174/157015907781695900.

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26

Dhingra, Anuradha y Noga Vardi. "mGlu receptors in the retina". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1, n.º 5 (22 de marzo de 2012): 641–53. http://dx.doi.org/10.1002/wmts.43.

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Durand, Daniela, Lila Carniglia y Mercedes Lasaga. "mGlu receptors in endocrine organs". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1, n.º 1 (19 de octubre de 2011): 78–84. http://dx.doi.org/10.1002/wmts.9.

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DOHERTY, Andrew J., Victoria COUTINHO, Graham L. COLLINGRIDGE y Jeremy M. HENLEY. "Rapid internalization and surface expression of a functional, fluorescently tagged G-protein-coupled glutamate receptor". Biochemical Journal 341, n.º 2 (8 de julio de 1999): 415–22. http://dx.doi.org/10.1042/bj3410415.

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L-Glutamate is the principal excitatory neurotransmitter in the vertebrate central nervous system, where it mediates many of its actions via G-protein-coupled metabotropic glutamate (mGlu) receptors. Since little is known about the dynamics of mGlu receptors at the plasma membrane, we have constructed a fusion protein comprising the mGlu receptor subtype 1α (mGlu1α) and green fluorescent protein (GFP). Using imaging of Ca2+ release from intracellular stores as a functional assay, the agonist pharmacology of this fluorescently tagged receptor was found to be similar to that of the wild-type receptor when expressed in HEK-293 cells. Receptor movement and function were measured simultaneously by combined imaging of Ca2+, using fura-red, and GFP fluorescence in single cells. Exposure to agonist induced a rapid loss of up to 30% of membrane-associated fluorescence, with a corresponding decrease in the functional response. Following removal of the agonist there was recovery of both the membrane fluorescence and the functional response. These data suggest that the surface expression of G-protein-coupled glutamate receptors might be rapidly regulated in response to agonist activation.

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Llinas del Torrent, Claudia, Laura Pérez-Benito y Gary Tresadern. "Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors". Molecules 24, n.º 6 (20 de marzo de 2019): 1098. http://dx.doi.org/10.3390/molecules24061098.

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Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.

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Jourdain, Vincent A., Nicolas Morin, Laurent Grégoire, Marc Morissette y Thérèse Di Paolo. "Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy". Journal of Neurosurgery 123, n.º 6 (diciembre de 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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Cho, Kwangwook y Zafar I. Bashir. "Cooperation between mglu receptors: a depressing mechanism?" Trends in Neurosciences 25, n.º 8 (agosto de 2002): 405–11. http://dx.doi.org/10.1016/s0166-2236(02)02228-2.

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Roberts, P. J., N. J. Toms, J. S. Bedingfield, D. E. Jane y N. K. Thomas. "Towards the pharmacological characterization of mGlu receptors". Neuropharmacology 35, n.º 6 (junio de 1996): A25. http://dx.doi.org/10.1016/0028-3908(96)84747-2.

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Salt, T. E. "Metabotropic glutamate (mGlu) receptors and nociceptive processing". Drug Development Research 54, n.º 3 (noviembre de 2001): 129–39. http://dx.doi.org/10.1002/ddr.10012.

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Mazzitelli, Mariacristina, Peyton Presto, Nico Antenucci, Shakira Meltan y Volker Neugebauer. "Recent Advances in the Modulation of Pain by the Metabotropic Glutamate Receptors". Cells 11, n.º 16 (21 de agosto de 2022): 2608. http://dx.doi.org/10.3390/cells11162608.

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Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological and signaling properties. mGluRs mediate several physiological functions such as neuronal excitability and synaptic plasticity, but they have also been implicated in numerous pathological conditions including pain. The availability of new and more selective allosteric modulators together with the canonical orthosteric ligands and transgenic technologies has led to significant advances in our knowledge about the role of the specific mGluR subtypes in the pathophysiological mechanisms of various diseases. Although development of successful compounds acting on mGluRs for clinical use has been scarce, the subtype-specific-pharmacological manipulation might be a compelling approach for the treatment of several disorders in humans, including pain; this review aims to summarize and update on preclinical evidence for the roles of different mGluRs in the pain system and discusses knowledge gaps regarding mGluR-related sex differences and neuroimmune signaling in pain.

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Hu, Hui-Juan y Robert W. Gereau. "Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn". Journal of Neurophysiology 105, n.º 6 (junio de 2011): 3010–21. http://dx.doi.org/10.1152/jn.01050.2010.

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Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

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Francisco Navarro, José, María Jesús Luque y Mercedes Martín-López. "Effects of LY379268, A Selective Agonist of mGLu2/3 Receptors, on Isolation-Induced Aggression in Male Mice". Open Pharmacology Journal 3, n.º 1 (20 de febrero de 2009): 17–20. http://dx.doi.org/10.2174/1874143600903010017.

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Recent studies indicate that glutamate metabotropic receptors (mGlu) 1 and 5 are involved in the regulation of aggressive behaviour. Brain distribution of mGlu2/3 receptors suggests that they may also play important roles in emotional responses, including aggression. This study examines the effects of LY379268 (0.25- 4 mg/kg, ip), a selective agonist of the mGlu2/3 receptors, on agonistic interactions between male mice using an animal model of isolation-induced aggression. Individually housed mice were exposed to anosmic “standard opponents” 30 min after drug administration. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. LY379268 (2 mg/kg) significantly reduced attack behaviour, as compared with the control group, without affecting immobility, whereas the highest dose of the drug (4 mg/kg) also decreased offensive behaviours (threat and attack), but with a marked increase of immobility (non-selective effect). These results indicate that mGlu2/3 receptors might be implicated in the modulation of aggression.

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Stansley, Branden J. y P. Jeffrey Conn. "Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors". Trends in Pharmacological Sciences 40, n.º 4 (abril de 2019): 240–52. http://dx.doi.org/10.1016/j.tips.2019.02.006.

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Chaki, Shigeyuki y Kenichi Fukumoto. "mGlu receptors as potential targets for novel antidepressants". Current Opinion in Pharmacology 38 (febrero de 2018): 24–30. http://dx.doi.org/10.1016/j.coph.2018.02.001.

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Hedberg, Thomas G., Ellen F. Sperber, Jana Velíšková y Solomon L. Moshé. "Laminar and Temporal Heterogeneity of NMDA/Metabotropic Glutamate Receptor Binding in Posterior Cingulate Cortex". Journal of Neurophysiology 84, n.º 4 (1 de octubre de 2000): 1881–87. http://dx.doi.org/10.1152/jn.2000.84.4.1881.

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Both N-methyl-d-aspartate (NMDA) and quisqualate/AMPA-insensitive metabotropic glutamate (mGlu) receptors mediate plasticity induction in neocortex, but their interlaminar distribution in cortical microcircuits is largely unknown. We used (+)3H-MK801 and3H-glutamate binding plus saturating concentrations of NMDA, AMPA, and quisqualate to autoradiographically map NMDA and mGlu receptor sites by lamina in posterior cingulate cortex in adult male rats. Specific binding at NMDA receptor sites in laminae II/III and VI was significantly reduced in comparison to other laminae. Brains prepared from rats killed during dark phase of a 12h/12h light/dark cycle showed a mean 129% increase in overall (+)3H-MK801 binding versus light phase brains but retained reduced binding densities in laminae II/III and VI. In contrast to NMDA findings, specific binding at mGlu sites was consistently elevated during light phase in both laminae II/III and VI. Specific 3H-glutamate binding in dark-phase brains showed an overall 147% increase versus light phase binding but did not retain significant interlaminar heterogeneity. Interpreted in accordance with our physiologically derived models of hippocampo-cortical microcircuitry, these results suggest that spatial and temporal variations in glutamate receptor distribution may play an important role in intracingulate neural processing of afferent input from hippocampus.

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Pilc, Andrzej y Shigeyuki Chaki. "Role of mGlu receptors in psychiatric disorders – Recent advances". Pharmacology Biochemistry and Behavior 232 (noviembre de 2023): 173639. http://dx.doi.org/10.1016/j.pbb.2023.173639.

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Cieślik, Paulina, Adrianna Radulska, Iwona Pelikant-Małecka, Agata Płoska, Leszek Kalinowski y 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, n.º 11 (6 de junio de 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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Fukuyama, Kouji, Eishi Motomura y Motohiro Okada. "A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine". Biomolecules 13, n.º 9 (23 de agosto de 2023): 1288. http://dx.doi.org/10.3390/biom13091288.

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Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-β-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine.

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Khan, Amna, Salman Khan y Yeong Shik Kim. "Insight into Pain Modulation: Nociceptors Sensitization and Therapeutic Targets". Current Drug Targets 20, n.º 7 (9 de mayo de 2019): 775–88. http://dx.doi.org/10.2174/1389450120666190131114244.

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Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.

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Wierońska, Joanna M., Paulina Cieślik, Grzegorz Burnat y Leszek Kalinowski. "Activation of Metabotropic Glutamate Receptor (mGlu2) and Muscarinic Receptors (M1, M4, and M5), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression, and cGMP Synthesis". Biomolecules 13, n.º 7 (30 de junio de 2023): 1064. http://dx.doi.org/10.3390/biom13071064.

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The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M1, M4, and M5 receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu2 receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GRIN2B GluN2B-NMDA expression.

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Bonsi, P., P. Platania, G. Martella, G. Madeo, D. Vita, A. Tassone, G. Bernardi y A. Pisani. "Distinct roles of group I mGlu receptors in striatal function". Neuropharmacology 55, n.º 4 (septiembre de 2008): 392–95. http://dx.doi.org/10.1016/j.neuropharm.2008.05.020.

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46

Nimitvilai, Sudarat, Maureen A. McElvain, Devinder S. Arora y Mark S. Brodie. "Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to Gq". Journal of Neurophysiology 108, n.º 1 (1 de julio de 2012): 263–74. http://dx.doi.org/10.1152/jn.01137.2011.

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Putative dopaminergic (pDAergic) ventral tegmental area neurons play an important role in brain pathways related to addiction. Extended exposure of pDAergic neurons to moderate concentrations of dopamine (DA) results in a time-dependent decrease in sensitivity of pDAergic neurons to DA inhibition, a process called dopamine inhibition reversal (DIR). We have shown that DIR is mediated by phospholipase C and conventional protein kinase C through concurrent stimulation of D2 and D1-like receptors. In the present study, we further characterized this phenomenon by using extracellular recordings in brain slices to examine whether DIR is linked to phosphatidylinositol (PI) or adenylate cyclase (AC) second-messenger pathways. A D1-like dopaminergic agonist associated with PI turnover (SKF83959), but not one linked to AC (SKF83822), promoted reversal of inhibition produced by quinpirole, a dopamine D2-selective agonist. Other neurotransmitter receptors linked to PI turnover include serotonin 5-HT2, α1-adrenergic, neurotensin, and group I metabotropic glutamate (mGlu) receptors. Both serotonin and neurotensin produced significant reversal of quinpirole inhibition, but agonists of α1-adrenergic and group I mGlu receptors failed to significantly reverse quinpirole inhibition. These results indicate that some agonists that stimulate PI turnover can facilitate desensitization of D2 receptors but that there may be other factors in addition to PI that control that interaction.

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Manahan-Vaughan, Denise. "Regulation of hippocampal information encoding by metabotopic glutamate receptors". Neuroforum 24, n.º 3 (28 de agosto de 2018): A121—A126. http://dx.doi.org/10.1515/nf-2018-a007.

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Abstract The hippocampus supports the acquisition of both spatial representations and long-term spatial memory. This is enabled by a triumvirate of physiological processes comprising information organisation and transfer by means of neuronal oscillations, creation of context-dependent spatial maps by means of place cells, and long-term storage of spatial experience by means of synaptic plasticity. All three processes are enabled by the glutamatergic system. Glutamate binding to ionotropic glutamate receptors enables both fast excitatory synaptic transmission (via AMPA receptors) and the initiation of long-term synaptic storage (via NMDA receptors). But glutamate also binds to metabotropic glutamate (mGlu) receptors. These receptors not only contribute to the stability of hippocampal encoding and the longevity of synaptic plasticity, they can also support synaptic information storage independent of NMDA receptor activation and are important for the acquisition and retention of long-term memory.

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Chinestra, P., L. Aniksztejn, D. Diabira y Y. Ben-Ari. "(RS)-alpha-methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons". Journal of Neurophysiology 70, n.º 6 (1 de diciembre de 1993): 2684–89. http://dx.doi.org/10.1152/jn.1993.70.6.2684.

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1. The effects of the putative antagonist of metabotropic glutamate receptors (mGluR), (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), were investigated in CA1 hippocampal neurons using intracellular and extracellular recordings. 2. MCPG (0.5 mM) did not antagonize the characteristic block of the slow afterhyperpolarization and spike accomodation produced by the selective mGluR agonist, 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (30 microM). 3. MCPG (0.5 mM) did not prevent the inward current produced by 1S,3R-ACPD (30 microM) [240 +/- 14 and 255 +/- 21 pA (mean +/- SD) in the absence and in presence of MCPG, respectively]. 4. MCPG (0.5 mM, 10 min) did not prevent the presynaptically mediated reduction by 1S,3R-ACPD (50 microM, 10 min) of the field excitatory postsynaptic potential (EPSP) (51 +/- 7 and 64 +/- 10% in the absence and in presence of MCPG, respectively). 5. MCPG (0.5 mM) did not prevent the induction of long-term potentiation by a high-frequency tetanic stimulation of Schaffer collaterals (100 Hz, 1 s) (+61 +/- 5 and +67 +/- 16% increase in the absence and presence of MCPG, respectively). 6. These observations suggest that MCPG is not an antagonist of the subtypes of mGlu receptors that are present in CA1 pyramidal neuron. Possible selectivity of this compound for specific mGluRs is discussed in view of the regional distribution of metabotropic receptors in the hippocampus.

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Fitzjohn, S. M., Z. A. Bortolotto, M. J. Palmer, A. J. Doherty, P. L. Ornstein, D. D. Schoepp, A. E. Kingston, D. Lodge y G. L. Collingridge. "The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity". Neuropharmacology 37, n.º 12 (diciembre de 1998): 1445–58. http://dx.doi.org/10.1016/s0028-3908(98)00145-2.

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Estrela, Karolyne A. R., Lisa Senninger, Josephine Arndt, Melanie Kabas, Ferdinand Schmid, Larissa Dillmann, Sophia Auer, Thomas Stepfer, Peter J. Flor y Nicole Uschold-Schmidt. "Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice". Cells 11, n.º 11 (2 de junio de 2022): 1817. http://dx.doi.org/10.3390/cells11111817.

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Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic–pituitary–adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in men.

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