L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors, such as GRM4. The metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors, have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group II and group III mGluRs are linked to the inhibition of the cyclic AMP cascade, but differ in their agonist selectivities. Group III agonists include L-2-amino-4-phosphonobutyrate (L-AP4) and L-serine-O-phosphate (summary by Wu et al., 1998).

Using a PCR strategy with primers based on consensus regions of rat mGluR1-5, Makoff et al. (1996) isolated partial cDNAs corresponding to the human homologs of these genes. By probing a cerebellum library with the partial human mGluR4 cDNA, the authors isolated additional mGluR4 cDNAs which between them contained the complete coding sequence for the human protein. The predicted 912-amino acid human mGluR4 protein shares 90% identity with rat mGluR4. Northern blot analysis of human tissues revealed that the approximately 5-kb mGluR4 mRNA was only expressed in brain. In situ hybridization to brain tissues indicated that human mGluR4 mRNA, like that of rat mGluR4, has a narrow distribution. In both organisms, the highest level of expression was detected in the granule cells of the cerebellum. Wu et al. (1998) isolated cDNAs encoding 3 human group III mGluRs, mGluR4, mGluR7 (604101) and mGluR8 (601116), and compared the pharmacologic properties of these receptors.

By database analysis, Bjarnadottir et al. (2005) identified GRM4 orthologs in mouse and fish. The deduced mouse protein contains 912 amino acids.

Bjarnadottir et al. (2005) determined that the GRM4 gene contains 7 exons.

Barbon et al. (2000) mapped the GRM4 gene to chromosome 6p21.3 by radiation hybrid mapping.

Bjarnadottir et al. (2005) mapped the mouse Grm4 gene to chromosome 17.

To provide a better understanding of the L-AP4 receptors, Pekhletski et al. (1996) generated knockout mice lacking the mGluR4 gene. The mutant mice did not display any gross motor abnormalities, impairments of novelty-induced exploratory behaviors, or alterations in fine motor coordination. However, they were deficient on the rotating rod motor-learning test, suggesting that they may have an impaired ability to learn complex motor tasks. Analysis of presynaptic short-term synaptic plasticity at the parallel fiber-Purkinje cell synapse demonstrated that paired-pulse facilitation and post-tetanic potentiation were impaired in the mutant mice, although long-term depression was unaffected. Pekhletski et al. (1996) concluded that an important function of mGluR4 is to provide a presynaptic mechanism for maintaining synaptic efficacy during repetitive activation, and that the presence of mGluR4 at the parallel fiber-Purkinje cell synapse is required for maintaining normal motor function. Gerlai et al. (1998) found that mGluR4 mutant mice exhibited significantly accelerated learning performance in a spatial reversal learning task. In a probe trial administered 6 weeks posttraining, the mice showed impaired spatial accuracy. These results suggested that mGluR4 mutant mice differ in their ability to learn and integrate new spatial information into previously formed memory traces and that their use of stored spatial information is altered.

Fallarino et al. (2010) observed that mGluR4-null mice were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS; 126200), and developed immune responses dominated by IL17 (603149)-producing T helper (TH17) cells. MGluR4 was constitutively expressed on dendritic cells isolated from wildtype mice. Signaling through mGluR4 decreased commitment to the TH17 phenotype by decreasing intracellular cAMP. Treatment of wildtype mice with a selective mGluR4 enhancer increased EAE resistance and offered a protective response via a shift toward regulatory CD4+ T cells. In contrast, dendritic cells from mGluR4-null mice showed defective mGluR4 signaling with resultant bias toward the TH17 phenotype. The findings provided evidence that glutamate acts at the interface between the nervous and immune systems, with mGluR4 present on dendritic cells in the central nervous system. Fallarino et al. (2010) suggested that the high amounts of glutamate associated with neuroinflammation might reflect a counterregulatory mechanism that is protective in nature by decreasing activation of pathogenic IL17-producing T cells.