Disease relevance of Grm1

• Like striatal neurons, cerebral cortical neurons express a mGluR that is able to inhibit AC both in intact cells and in membrane preparations, via a pertussis toxin-sensitive G protein [1].
• crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1) [2].
• Based on these earlier studies and results from our recent work, we predict that inhibition of Grm1 signaling and its downstream cascade may potentially provide new, effective therapies for melanoma patients [3].
• mGluR1 mutant mice are viable but show characteristic cerebellar symptoms such as ataxic gait and intention tremor [4].
• To determine whether the coupling mode of mGluRs to ADP-ribosyl cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108-15 neuroblastoma x glioma hybrid cells [5].

Psychiatry related information on Grm1

• We found that acute amphetamine injection increased motor activity in both mutant and control mice in a dose-dependent manner (1, 4, and 12 mg/kg, i.p.). However, the overall motor responses of mGluR1 -/- mice to all three doses of amphetamine were significantly greater than those of wild-type +/+ mice [6].
• mGluR1 in cerebellar Purkinje cells is required for normal association of temporally contiguous stimuli in classical conditioning [7].
• Thus, a heightened mGluR response does not account for the critical period in development [8].
• CONCLUSIONS: The present findings suggest complex effects of GCP II inhibition on morphine dependence and tolerance and imply a role of mGluR II in the actions of 2-MPPA [9].
• Therefore, the way homologous recombination was performed in ES cells demonstrated that gene replacement of mGluR1 by lacZ could be a powerful technique to disrupt a gene and at the same time study its endogenous expression [10].

High impact information on Grm1

• We generated a novel strain of mutant mouse with a deletion in the gene encoding metabotropic glutamate receptor 1 (mGluR1) [11].
• Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice [11].
• In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels [12].
• They have no gross anatomical or basic electrophysiological abnormalities in either the cerebellum or hippocampus, but they show impaired cerebellar long-term depression and hippocampal mossy fibre long-term potentiation. mGluR1-deficient mice should therefore be valuable models for studying synaptic plasticity [13].
• Metabotropic glutamate receptor 1 (mGluR1) is a member of a large family of G-protein-coupled glutamate receptors, the physiological functions of which are largely unknown [13].

Chemical compound and disease context of Grm1

• Subcutaneous injection of a group II mGluR agonist, 2R,4R 4-aminopyrrolidine-2,4-dicarboxylate (APDC), did not alter thermal sensitivity but blocked prostaglandin E2 (PGE2)-induced thermal hyperalgesia [14].
• The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice [15].
• The results suggest that group I mGluR antagonists may have a neuroprotective role against MPTP-induced degeneration of DA neurons and thus probably also against neurodegenerative processes occurring in Parkinson's disease [16].

Biological context of Grm1

• Altered agonist sensitivity and desensitization of neuronal mGluR1 responses in knock-in mice by a single amino acid substitution at the PKC phosphorylation site [17].
• Expression of the metabotropic glutamate receptor type 1 alpha (mGluR1 alpha) and the non-N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor type 1 (GluR1) in mouse brain was investigated using the antibodies raised against the synthetic peptides corresponding to their C-terminal amino acid sequences [18].
• Using linkage analysis, we mapped the crv4 locus to the proximal region of chromosome 10, at the location of the Grm1 gene [2].
• Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-beta1-/- mice during barrel development [19].
• 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) [20].

Anatomical context of Grm1

• We also present evidence for a new mGluR subtype expressed in glial cells [1].
• We examined the effect of this D854T substitution on Ca2+ and current responses mediated by mGluR1 in cultured cerebellar Purkinje cells [17].
• We showed that mGluR1 alpha and GluR1 expression within the first 3 postnatal weeks undergoes dramatic changes in time and space, i.e., in the hippocampus and cerebellum [18].
• In the wild-type and mGluR1 mutant PCs, CF-induced Ca(2+) signals involved both proximal and distal dendrites [21].
• Grm1 is a seven transmembrane domain G-protein coupled receptor that is normally expressed and functional in the central nervous system [3].

Associations of Grm1 with chemical compounds

• Application of group I metabotropic glutamate receptor (mGluR) agonists elicits seizure discharges in vivo and prolonged ictal-like activity in in vitro brain slices [22].
• 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 [22].
• However, only glutamate and aspartate, and not quisqualate, 2-(carboxycyclopropyl)glycine, trans-1-aminocyclopentane-1,3-dicarboxylate, or L-2-amino-4-phosphonobutyrate, were agonists for this glial mGluR [1].
• 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 [23].
• The mGluR1 D854T mutation abolished the responsiveness of mGluR1 to low concentrations of DHPG (0.5-500 nM) and reduced its desensitization during prolonged agonist application. mGluR1 D854T homozygous mutants showed no apparent behavioural abnormality as analysed by motor movement tests [17].

Physical interactions of Grm1

• In a previous work, we demonstrated that striatal neurons in primary culture expressed a mGluR that is negatively coupled to AC and that has a pharmacology different from that of mGluR2 [1].
• Striatal glial cells also expressed a mGluR negatively coupled to AC via a pertussis toxin-sensitive G protein [1].
• These results suggest that GT1-7 cells express a novel mGluR subtype positively coupled to adenylate cyclase, which shares the same transduction pathway of other classical receptors coupled with a Gs-type of GTP-binding protein [24].

Regulatory relationships of Grm1

• Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine [25].
• In the adult cerebellum, mGluR1 alpha is intensely expressed in Purkinje neurons and GluR1 in Bergmann glial cells [18].

Other interactions of Grm1

• Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS [25].
• Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS [25].
• Roles of glutamate receptor delta 2 subunit (GluRdelta 2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development [21].
• Several cDNAs coding for metabotropic glutamate receptors (mGluR1-7) have now been isolated. mGluR1 and -5 are positively coupled to phospholipase C, whereas mGluR2, -3, -4, -6, and -7 are negatively coupled to adenylyl cyclase (AC) when they are expressed in Chinese hamster ovary or baby hamster kidney cells [1].
• This mGluR has a pharmacological profile similar to that of mGluR3, because quisqualate is active at relatively low concentrations (EC50 < 100 microM) [1].

Analytical, diagnostic and therapeutic context of Grm1

• We then examined mGluR1-induced inward currents carried by nonselective cation channels during whole-cell recordings from cultured Purkinje cells [17].
• Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests [26].
• Thus, the nocifensive response to intrathecal injection of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG) is significantly potentiated seven days following Complete Freund's Adjuvant (CFA)-induced inflammation of the hind paw [27].
• Mice received mGluR ligands by intracerebroventricular (i.c.v.) infusion prior to a subcutaneous injection of PTZ and the latency to onset of tonic convulsions was recorded [28].
• Therefore, this mouse is the first animal model in which effects of mGluR1 deficiency outside PCs can be studied without cerebellar dysfunction [7].

References