Disease relevance of Grm5

• Reduced stress-induced hyperthermia in mGluR5 knockout mice [1].
• Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively [2].
• Modulation of mGluR5 signaling may allow amelioration of symptoms of Fragile X Syndrome [3].
• The NMDA-mGluR5 interaction might play an important modulatory role in the final excitatory drive from corticostriatal afferents and suggests that drugs acting at mGluR5 might prove useful for the treatment of movement disorders involving the striatum [4].
• Those findings combined with the present in vitro results lead us to speculate that mGluR5 expression may also be altered in vivo during reactive gliosis [5].

Psychiatry related information on Grm5

• Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice [6].
• The PPI deficit seen in the mGluR5 KO mice is not mimicked by acute administration of an mGluR5 antagonist, and is therefore most likely due to compensatory alterations in neuronal circuitry occurring during development independent of maternal behaviors in the postnatal environment [7].
• Glutamatergic neurotransmission plays a critical role in addictive behaviors, and recent evidence indicates that genetic or pharmacological inactivation of the type 5 metabotropic glutamate receptor (mGluR5) reduces the self-administration of cocaine, nicotine, and alcohol [8].
• Similarly, the mGluR5 antagonist did not modulate the antiseizure activity of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock in mice [9].

High impact information on Grm5

• Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells [10].
• Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5 [10].
• Our data indicate that PLC-beta1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated [11].
• Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice [6].
• Here we report the presence of phospholipase C-coupled group I mGluRs (mGluR1 and mGluR5) outside the central nervous system on peripheral unmyelinated sensory afferents [12].

Chemical compound and disease context of Grm5

• It hs been suggested that metabotropic glutamate receptor subtype 5 (mGluR5) play a role in the expression of anxiety, based on anxiolytic-like effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) in rodent models of anxiety, including stress-induced hyperthermia (SIH) [1].
• Neuroprotective effects of MTEP, a selective mGluR5 antagonists and neuropeptide Y on the kainate-induced toxicity in primary neuronal cultures [13].

Biological context of Grm5

• One of these, long-term potentiation of intrinsic excitability, is intrinsic in expression and requires mGluR5 activation [14].
• These findings support the idea that the increased mGluR5 following repeated treatment with morphine leads to enhanced neuronal excitability and synaptic transmission in the dorsal horn of the spinal cord and, in turn, suppresses the morphine-induced antinociception in mice [15].
• Here, we show that developing murine cortical neurons exhibit calcium oscillations in response to direct activation of the mGluR5 subtype of the group I metabotropic glutamate receptor (mGluR) [16].
• This interaction was confirmed by reverse overlay, and a single point mutation to the mGluR5-CT was found to completely disrupt the interaction [17].
• Therefore, mGluR5 antagonists were able to rescue two of the major phenotypes of the FX mouse [3].

Anatomical context of Grm5

• Homozygous null mutation of either PLC-beta1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation [11].
• Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the CA3 region, an NMDAR-independent pathway [18].
• Using the receptor binding assay, we found here that the number of mGluR5 in the mouse spinal cord was significantly increased by repeated treatment with morphine [15].
• Double-labeling experiments showed that the increased mGluR5 was predominantly expressed in the neurons and sparsely expressed in the processes of astrocytes following repeated treatment with morphine [15].
• D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons [2].

Associations of Grm5 with chemical compounds

• The mGluR1 antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385; 25-100 microM) and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10-50 microM), applied separately, significantly reduced the duration of the synchronized discharges [19].
• The selective mGluR-1a antagonist LY367385 and the mGluR-5 antagonist MPEP reversibly blocked the field potential oscillations, whereas the group II mGluR antagonist LY341495 did not block the activity [20].
• Most previous studies have focused on the group I metabotropic glutamate receptors (mGluR1 and mGluR5) and activation of phospholipase C signaling by these receptors in modulating nociception [21].
• This effect was mimicked by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), a selective agonist of mGluR2/R3 receptors, but not by quisqualate at a concentration that stimulated inositol phosphate (InsP) synthesis, showing that mGluR1 and mGluR5 did not participate to this mechanism [22].
• In the present study, we found that either intrathecal (i.t.) or subcutaneous (s.c.) injection of the selective metabotropic glutamate receptor 5 (mGluR5) antagonist, methyl-6-(phenylethynyl)-pyridine hydrochloride (MPEP), attenuated the development of tolerance to morphine-induced antinociception [15].

Co-localisations of Grm5

• By double immunofluorescence, Galphaq/Galpha11 was extensively colocalized with metabotropic glutamate receptor mGluR1alpha in dendritic spines of PCs and with mGluR5 in those of hippocampal pyramidal cells [23].

Regulatory relationships of Grm5

• The results suggest that mGluR1 and mGluR5 are activated synaptically during prolonged epileptiform discharges induced by bicuculline and 4-AP [19].
• Three Homer genes regulate the activity of metabotropic glutamate receptors mGluR1a and mGluR5 and their coupling to releasable intracellular Ca2+ pools and ion channels [24].

Other interactions of Grm5

• Therefore, the N-terminal portion of Homer1d may facilitate trafficking of Homer1-mGluR5 complex from the ER to the PM [25].
• The effects of these antagonists were additive when applied together, suggesting that mGluR1 and mGluR5 exert independent actions on the epileptiform bursts [19].
• We propose that mGluR5 plays a key regulatory role in NMDAR-dependent LTP [18].
• The mGluR1, but not mGluR5, subclass of metabotropic glutamate receptors uses CK1 to inhibit NMDA-mediated synaptic currents [26].
• Gene targeting reveals a role for the glutamate receptors mGluR5 and GluR2 in learning and memory [27].
• We provide evidence that GRK2 mediates phosphorylation-independent mGluR5 desensitization and internalization in neurons [28].

Analytical, diagnostic and therapeutic context of Grm5

• Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests [29].
• Full-length mGluR5 robustly associated with full-length NHERF-2 in cells, as assessed by co-immunoprecipitation and confocal microscopy experiments [17].
• The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice [30].
• High resolution immunoelectron microscopy was used to study subcellular localization patterns of three metabotropic glutamate receptor subtypes (mGluR1alpha, mGluR5, and mGluR2/3) during postnatal development of mouse ventral posterior (VP) thalamic nucleus [31].
• PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed [32].

References