Alternative titles; symbols
HGNC Approved Gene Symbol: GRM5
Cytogenetic location: 11q14.2-q14.3 Genomic coordinates (GRCh38) : 11:88,504,642-89,065,982 (from NCBI)
L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that contain 7 membrane-spanning domains and a large extracellular N-terminal region. The group I receptors mGluR1 (604473) and mGluR5 activate phospholipase C (PLC; see 600220) (summary by Minakami et al., 1994).
By screening a human brain cDNA library with a rat mGluR1-alpha cDNA under low stringency conditions, Minakami et al. (1993) and Minakami et al. (1994) isolated human cDNAs encoding mGluR5. Minakami et al. (1993) identified a longer isoform of mGluR5 (mGluR5B), whereas Minakami et al. (1994) identified a splice variant encoding a shorter isoform (mGluR5A) and characterized the proteins. Both isoforms are present in rat, and the rat and human mGluR5B transcripts contain an identical 96-bp insertion (Minakami et al., 1993). The predicted human mGluR5A and mGluR5B isoforms contain 1,180 and 1,212 amino acids, respectively. Human and rat mGluR5A share 95% amino acid sequence identity. When expressed in Xenopus oocytes, both isoforms activated PLC in response to glutamate.
By database analysis, Bjarnadottir et al. (2005) identified GRM5 orthologs in mouse and fish. The deduced mouse protein contains 1,010 amino acids.
Minakami et al. (1994) found no clear differences between the pharmacologic profiles of splice variants mGluR5A and mGluR5B.
G protein-coupled receptors transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations. 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. Ango et al. (2001) demonstrated that in neurons, the constitutive activity of these receptors is controlled by Homer proteins (e.g., 604798), which bind directly to the receptors' carboxy-terminal intracellular domains. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a, induces constitutive activity in mGluR1a or mGluR5. Ango et al. (2001) concluded that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.
One prominent action of group I mGluRs is to protect neurons from apoptotic death (Copani et al., 1995; Maiese et al., 2000). Using immunoprecipitation studies in rat, Rong et al. (2003) found that the PI3 kinase enhancer PIKE-L (605476) binds to Homer-1C, an adaptor protein that is localized to postsynaptic densities. Activation of mGluR5 enhanced formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3K activity and prevention of apoptosis in cultured neurons.
Neuronal dense granules transport mRNAs into dendrites for subsequent site-specific utilization at synapses. Some dense granules contain aggregates of translationally silent polysomes. During active protein synthesis, the structure of the granule relaxes into lighter translating polysomes. Aschrafi et al. (2005) found that Fmr1 (309550)-knockout mouse brains showed a lower amount of dense granules than wildtype mouse brains. The Fmr1-knockout mice also showed elevated Grm5-induced translation. Injection of a Grm5-specific inhibitor increased the dense granule peak in both wildtype and Fmr1-knockout mouse brains and blocked Grm5-induced activity in hippocampal slices. Aschrafi et al. (2005) concluded that GRM5-induced translation from neuronal granules occurs at a higher rate in the absence of FMR1.
Wang et al. (2009) reported that Norbin (NCDN; 608458), a neuron-specific protein, physically interacts with mouse mGluR5 in vivo, increases the cell surface localization of the receptor, and positively regulates mGluR5 signaling. Genetic deletion of Norbin attenuated mGluR5-dependent stable changes in synaptic function measured as long-term depression or long-term potentiation of synaptic transmission in the hippocampus. As with mGluR5 knockout mice or mice treated with mGluR5-selective antagonists, Norbin knockout mice showed a behavioral phenotype associated with a rodent model of schizophrenia (see 181500), as indexed by alternations both in sensorimotor gating and psychotomimetic-induced locomotor activity.
In rodent cerebral cortex, there is a developmental switch from Nr2b- (GRIN2B; 138252) to Nr2a (GRIN2A; 138253)-containing NMDA receptors that is driven by activity and sensory experience. This subunit switch alters NMDA receptor function and influences synaptic plasticity. Using whole-cell patch-clamp recordings from CA1 pyramidal neurons of neonatal rats and mGlur5-knockout mice, Matta et al. (2011) found that the Nr2b-to-Nr2a switch was rapid and required mGlur5 in addition to NMDA receptor activation. Glutamate binding to mGlur5 led to activation of PLC (see 607120), followed by release of calcium from intracellular stores and activation of PKC (see 176960) by diacylglycerol. A similar Nr2b-to-Nr2a switch requiring mGlur5 occurred following visual stimulation at inputs onto layer 2/3 pyramidal neurons in mouse primary visual cortex.
Auerbach et al. (2011) used electrophysiologic and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2 (191092) heterozygote and Fmr1-null male mice to show that synaptic dysfunction caused by these mutations falls at opposite ends of a physiologic spectrum. Synaptic, biochemical, and cognitive defects in these mutants were corrected by treatments that modulated metabotropic Grm5 in opposite directions, and deficits in the mutants disappeared in mice bred to carry both mutations. Auerbach et al. (2011) concluded that normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioral impairments.
Using genomic analysis, immunoelectron microscopy, and 2-photon microscopy of astrocytic calcium ion signaling in vivo, Sun et al. (2013) found that astrocyte expression of mGluR5 is developmentally regulated and is undetectable after postnatal week 3 in the mouse. In contrast, mGluR3 (601115), whose activation inhibits adenylate cyclase but not calcium signaling, was expressed in astrocytes at all developmental stages. Sun et al. (2013) concluded that neuroglial signaling in the adult brain may therefore occur in a manner fundamentally distinct from that exhibited during development.
Using biochemistry, proteomics, and imaging in mice, Diering et al. (2017) found that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate-early gene Homer1a (604798) and signaling from group I metabotropic glutamate receptors mGluR1 (604473) and mGluR5, respectively. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators noradrenaline and adenosine, respectively. Diering et al. (2017) concluded that their data suggested that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.
Bjarnadottir et al. (2005) determined that the GRM5 gene contains 9 exons.
Crystal Structure
Dore et al. (2014) reported the crystal structure of the transmembrane domain of human GRM5 in complex with the negative allosteric modulator mavoglurant. The structure provided detailed insight into the architecture of the transmembrane domain of class C receptors, including the precise location of the allosteric binding site within the transmembrane domain and key microswitches that regulate receptor signaling.
By genomic sequence analysis, Bjarnadottir et al. (2005) mapped the GRM5 gene to chromosome 11q21.1. However, Gross (2012) mapped the GRM5 gene to chromosome 11q14.2-q14.3 based on an alignment of a GRM5 sequence (GenBank AY608336) with the genomic sequence (GRCh37).
Bjarnadottir et al. (2005) mapped the mouse Grm5 gene to chromosome 7.
Lu et al. (1997) generated mutant mice lacking mGluR5 expression. They found that the mutant mice were impaired in the acquisition and use of spatial information. Electrophysiologic measurements indicated that long-term potentiation (LTP) in the mutant mice was significantly reduced in the NMDA receptor (see 138249)-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 NMDA receptor-independent pathway. The authors proposed that mGluR5 plays a key regulatory role in NMDA receptor-dependent LTP and that LTP in the CA1 region may underlie spatial learning and memory.
In rats, Byrnes et al. (2009) found that intrathecal administration of an mGluR5 agonist after spinal cord injury resulted in increased functional motor recovery, decreased lesion volume, and increased white matter sparing. These changes were associated with an attenuated microglial inflammatory response, and immunohistochemical labeling showed that mGluR5 was present on microglia in the injured spinal cord. Stimulation of mGluR5 reduced microglial activation and decreased microglial-associated neurotoxicity in spinal cord microglia cultures. The findings suggested that antiinflammatory effects modulated by mGluR5 activation on microglia may have multipotential neuroprotective effects.
Ango, F., Prezeau, L., Muller, T., Tu, J. C., Xiao, B., Worley, P. F., Pin, J. P., Bockaert, J., Fagni, L. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411: 962-965, 2001. [PubMed: 11418862] [Full Text: https://doi.org/10.1038/35082096]
Aschrafi, A., Cunningham, B. A., Edelman, G. M., Vanderklish, P. W. The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc. Nat. Acad. Sci. 102: 2180-2185, 2005. [PubMed: 15684045] [Full Text: https://doi.org/10.1073/pnas.0409803102]
Auerbach, B. D., Osterweil, E. K., Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480: 63-68, 2011. [PubMed: 22113615] [Full Text: https://doi.org/10.1038/nature10658]
Bjarnadottir, T. K., Fredriksson, R., Schioth, H. B. The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste(1) and other related G protein-coupled receptors. Gene 362: 70-84, 2005. [PubMed: 16229975] [Full Text: https://doi.org/10.1016/j.gene.2005.07.029]
Byrnes, K. R., Stoica, B., Riccio, A., Pajoohesh-Ganji, A., Loane, D. J., Faden, A. I. Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents. Ann. Neurol. 66: 63-74, 2009. [PubMed: 19670441] [Full Text: https://doi.org/10.1002/ana.21673]
Copani, A., Bruno, V. M. G., Barresi, V., Battaglia, G., Condorelli, D. F., Nicoletti, F. Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture. J. Neurochem. 64: 101-108, 1995. [PubMed: 7798903] [Full Text: https://doi.org/10.1046/j.1471-4159.1995.64010101.x]
Diering, G. H., Nirujogi, R. S., Roth, R. H., Worley, P. F., Pandey, A., Huganir, R. L. Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355: 511-515, 2017. [PubMed: 28154077] [Full Text: https://doi.org/10.1126/science.aai8355]
Dore, A. S., Okrasa, K., Patel, J. C., Serrano-Vega, M., Bennett, K., Cooke, R. M., Errey, J. C., Jazayeri, A., Khan, S., Tehan, B., Weir, M., Wiggin, G. R., Marshall, F. H. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511: 557-562, 2014. [PubMed: 25042998] [Full Text: https://doi.org/10.1038/nature13396]
Gross, M. B. Personal Communication. Baltimore, Md. 4/19/2012.
Lu, Y. M., Jia, Z., Janus, C., Henderson, J. T., Gerlai, R., Wojtowicz, J. M., Roder, J. C. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17: 5196-5205, 1997. [PubMed: 9185557] [Full Text: https://doi.org/10.1523/JNEUROSCI.17-13-05196.1997]
Maiese, K., Vincent, A., Lin, S.-H., Shaw, T. Group I and group III metabotropic glutamate receptor subtypes provide enhanced neuroprotection. J. Neurosci. Res. 62: 257-272, 2000. [PubMed: 11020218] [Full Text: https://doi.org/10.1002/1097-4547(20001015)62:2<257::AID-JNR10>3.0.CO;2-H]
Matta, J. A., Ashby, M. C., Sanz-Clemente, A., Roche, K. W., Isaac, J. T. R. mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron 70: 339-351, 2011. [PubMed: 21521618] [Full Text: https://doi.org/10.1016/j.neuron.2011.02.045]
Minakami, R., Katsuki, F., Sugiyama, H. A variant of metabotropic glutamate receptor subtype 5: an evolutionally conserved insertion with no termination codon. Biochem. Biophys. Res. Commun. 194: 622-627, 1993. [PubMed: 7688218] [Full Text: https://doi.org/10.1006/bbrc.1993.1866]
Minakami, R., Katsuki, F., Yamamoto, T., Nakamura, K., Sugiyama, H. Molecular cloning and the functional expression of two isoforms of human metabotropic glutamate receptor subtype 5. Biochem. Biophys. Res. Commun. 199: 1136-1143, 1994. [PubMed: 7908515] [Full Text: https://doi.org/10.1006/bbrc.1994.1349]
Rong, R., Ahn, J.-Y., Huang, H., Nagata, E., Kalman, D., Kapp, J. A., Tu, J., Worley, P. F., Snyder, S. H., Ye, K. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nature Neurosci. 6: 1153-1161, 2003. [PubMed: 14528310] [Full Text: https://doi.org/10.1038/nn1134]
Sun, W., McConnell, E., Pare, J.-F., Xu, Q., Chen, M., Peng, W., Lovatt, D., Han, X., Smith, Y., Nedergaard, M. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339: 197-200, 2013. [PubMed: 23307741] [Full Text: https://doi.org/10.1126/science.1226740]
Wang, H., Westin, L., Nong, Y., Birnbaum, S., Bendor, J., Brismar, H., Nestler, E., Aperia, A., Flajolet, M., Greengard, P. Norbin is an endogenous regulator of metabotropic glutamate receptor 5 signaling. Science 326: 1554-1557, 2009. [PubMed: 20007903] [Full Text: https://doi.org/10.1126/science.1178496]