Disease relevance of GRM5

• A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease [1].
• The presence of a receptor for glutamate, the major excitatory neurotransmitter, in human melanocytes is intriguing. mGlu5 receptors may be involved in the control of melanocyte proliferation (and perhaps in other functions), but harbor a potential toxicity and may therefore contribute to cell damage under pathological conditions [2].
• Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins [3].
• Antagonists acting on mGlu1 or mGlu5 receptors are anticonvulsant against 3,5-dihydroxyphenylglycine (DHPG)-induced seizures and in mouse models of generalized motor seizures and absence seizures [4].
• In order to confirm the possible expression of mGluR5 in cell of glial origin we examined the mRNA levels for this receptor in tissue samples from human gliomas obtained after surgical resection of the tumors: only 1 sample (grade II astrocytoma), out of 8 examined, showed the presence of mGluR5 mRNA [5].

Psychiatry related information on GRM5

• These include mGluR1 antagonists in pain, mGluR5 antagonists in anxiety, pain and drug abuse and mGluR5 positive allosteric modulators in schizophrenia [6].
• CONCLUSIONS: These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity [7].
• Here, we used the Y-maze spatial alternation task and examined whether enhancement of intrinsic mGluR5 activity immediately after learning, i.e. during a critical period for memory consolidation, would have any consequences on long-term memory retention in rats [8].
• At all stages of human development, a strong mGluR5 immunoreactivity was observed in the dorsal roots and in the dorsal and dorsolateral funiculi with maximum levels of staining at week 12 of gestation [9].

High impact information on GRM5

• CONCLUSIONS: mGluR5 antagonists potently inhibit TLESR and reflux in ferrets, implicating mGluR5 in the mechanism of TLESR. mGluR5 antagonists are therefore promising as therapy for patients with GERD [10].
• In accord with a role of mGluR5 in the regulation of ongoing translation in vivo, we observed that the phosphorylation of several initiation factors in response to application of the mGluR1/5 agonist S-3,5-dihydroxyphenylglycine in vitro was blocked by methyl-6-(phenylethynyl)pyridine [11].
• Replacements of lysine residues with arginine showed that Siah1A-mediated ubiquitination occurs at multiple lysine residues spanning both the seven-transmembrane region and carboxyl-terminal tail of mGluR5 [12].
• Group I mGluRs include mGluR1 and mGluR5, which are linked to the activation of phospholipase C; Groups II and III include all others and are negatively coupled to adenylyl cyclases [13].
• The two members of the group I metabotropic glutamate receptor family, mGluR1 and mGluR5, both couple to G(q) to mediate rises in intracellular calcium [14].

Chemical compound and disease context of GRM5

• Second, we show that the mechanism of BMAA toxicity is threefold: it is an agonist for NMDA and mGluR5 receptors, and induces oxidative stress [15].
• Neuroprotective effects of MTEP, a selective mGluR5 antagonists and neuropeptide Y on the kainate-induced toxicity in primary neuronal cultures [16].

Biological context of GRM5

• Cultured human melanocytes express mGlu5 metabotropic glutamate (mGlu) receptors, as shown by RT-PCR, immunocytochemistry, Western blot analysis, and measurement of agonist-stimulated polyphosphoinositide hydrolysis [2].
• The mGlu5 receptor agonists (S)-3, 5-dihydroxyphenylglycine and quisqualate increased [(3)H-methyl]thymidine incorporation and melanocyte proliferation in subconfluent cultures, but impaired cell viability in confluent cultures [2].
• Application of the mGluR1/5 specific agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced calcium oscillations, which were inhibited by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) [17].
• Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors) [18].
• This is the first demonstration that an antagonist of mGlu5 receptors, like a majority of well-established antidepressants, induces hippocampal BDNF gene expression [19].

Anatomical context of GRM5

• 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 [1].
• Expression of functional mGlu5 metabotropic glutamate receptors in human melanocytes [2].
• Furthermore, immunocytochemical analysis identified mGluR5 in oligodendrocyte marker O4-positive OPCs [17].
• This condition mimics the morphology of reactive glial cells in vivo including an increased expression of mGluR5 protein (observed in pathological conditions) [3].
• Developmental dependence, the role of the kinases p38 MAPK and PKC, and the involvement of tumor necrosis factor-R1 in the induction of mGlu-5 LTD in the dentate gyrus [20].

Associations of GRM5 with chemical compounds

• Thus, mGluR3 and mGluR5 can critically and differentially modulate the expression of glutamate transporters and may represent interesting pharmacological targets to regulate the extracellular levels of glutamate in pathological conditions [3].
• 6. Expression of both mGlu1 and mGlu5 receptor mRNA by T lymphocytes and T-cell lines, as demonstrated by reverse transcriptase-PCR analysis, suggests that L-glutamate-mediated inhibition of AICD was exerted on T cells [21].
• Similarly, DTT reduced the increase in intracellular free Ca(2+) induced by glutamate in HEK-293 cells expressing mGlu5 receptors [22].
• In conclusion our data show that the only cloned metabotropic receptor linked to phosphoinositide hydrolysis, whose expression is detectable in cultured type-1 astrocytes, in mGluR5 [5].
• A short region of the mGluR5 C terminus is the critical determinant and differs from the analogous region of mGluR1alpha by a single amino acid residue, Thr-840, which is an aspartic acid (Asp-854) in mGluR1alpha [23].

Physical interactions of GRM5

• The G-protein coupled metabotropic glutamate receptor mGlu5 plays a pivotal role as a modulator of synaptic plasticity, ion channel activity and excitotoxicity [24].

Regulatory relationships of GRM5

• Single-cell intracellular calcium ([Ca2+]i) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+]i response in mGluR1-expressing and mGluR5-expressing cells, respectively [25].
• We now report that ES cells differentiating into embryoid bodies (EBs) progressively lose mGlu5 receptors and begin to express mGlu4 receptors at both mRNA and proteinc level [26].
• In contrast, mGluR5 alone or mGluR5 coexpressed with Homer 1a successfully travels through the secretory pathway to the plasma membrane [27].
• Inhibition of these processes reveals a tonic, mGlu5 receptor and PTK-dependent potentiation of NMDA receptors that can be augmented by either stimulating mGlu5 receptors or by inhibiting PTPs [28].

Other interactions of GRM5

• RESULTS: We detected mGluR3 and mGluR5 (but not mGluR1, 6 and 7) mRNAs in all of the samples examined [29].
• This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators [30].
• Signals for mGluR1 and mGluR5 were enriched in the dorsal horn, while mGluR4 mRNA was abundant in the ventral horn [31].
• Therefore, the large truncation of the C-terminal tail of mGlu5 does not have any apparent major effect on the potency and efficacy of agonists as measured by the [Ca(2+)](i) responses or by activation of recombinant G-protein coupled inwardly rectifying K(+) (GIRK) channel currents [24].
• Using site-directed mutagenesis, [3H]MPEP binding, a functional Ca2+ mobilization assay, and rhodopsin-based homology modeling, we identified eight residues (Pro-6543.36, Tyr-6583.40, Leu-7435.47, Thr-7806.44, Trp-7846.48, Phe-7876.51, Tyr-7916.55, and Ala-8097.47) that are crucial for MPEP-binding to rat mGlu5 receptors [32].

Analytical, diagnostic and therapeutic context of GRM5

• Our RT-PCR analysis detected mRNAs for mGluR3 and mGluR5 isoforms in OPCs [17].
• The expression of mGluR5 was also demonstrated in oligodendrocyte marker (O4 and O1) positive cells in white matter of postnatal 4- and 7-day-old rat brain sections using immunofluorescent double labelling and confocal microscopy [17].
• The mGluR5 receptor function was assessed in CG-4 OPCs with fura-2 microfluorometry [17].
• We now report that chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGlu5 receptor antagonist, increased hippocampal but reduced cortical BDNF mRNA level (Northern blot) [19].
• In situ hybridization showed that transcripts of both metabotropic glutamate receptor (mGluR) 1 and mGluR5 were expressed in motoneurons in both the resistant motor nucleus III and the vulnerable motor nucleus XII [33].

References