Disease relevance of GRM7

• The Tyr433Phe polymorphism of mGluR7 and a novel polymorphism in the mGluR8 gene located 29 bp after the termination codon (2756C/T) were investigated in case control association studies performed on DNA from more than 100 patients with idiopathic generalised epilepsy (IGE) [1].
• The mGluR7 cytoplasmic domain appended to the transmembrane portion of the vesicular stomatitis virus G protein and the ectodomain of human placental alkaline phosphatase is distributed over the entire cell surface in cultured neurons [2].

Psychiatry related information on GRM7

• Lack of polymorphism in genes encoding mGluR 7, mGluR 8, GABA(A) receptor alfa-6 subunit and nociceptin/orphanin FQ receptor and panic disorder [3].

High impact information on GRM7

• Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands [4].
• At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTPgammaS binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those of L-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of L-glutamate [4].
• Here we characterize an mGluR7-selective agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain [4].
• Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion [4].
• Bisulfite sequencing of GRM7 confirmed extensive CpG island methylation, and treatment with 5-aza-2'-deoxycytidine (decitabine) resulted in up-regulated expression of several genes in vitro with concurrent cellular depletion of DNMT1 protein [5].

Biological context of GRM7

• One such gene, the G protein-coupled metabotropic glutamate receptor 7 (GRM7), possibly inhibits cyclic AMP signaling in the induction of apoptosis [5].
• Assignment of the human metabotropic glutamate receptor gene GRM7 to chromosome 3p26.1-->p25.2 by radiation hybrid mapping [6].
• Both variants, present at high frequencies, failed to demonstrate any significant association with schizophrenia (mGluR7 [Tyr433Phe] allele: P=0.33; genotype: P=0.63; mGluR8 [2846-C/T] allele: P=0.72; genotype: P=0.63) [7].
• Human metabotropic glutamate receptor type 7 (mGluR7) cDNA clones were isolated from a medulla cDNA library [8].
• The sequence, which includes a polymorphism, has 92% DNA sequence identity with rat mGluR7 and the predicted protein sequence has 99% identity [8].

Anatomical context of GRM7

• In-situ hybridization studies on human brain sections showed that mGluR7 mRNA has a widespread distribution with highest levels in the hippocampal formation, cerebral cortex and cerebellum [8].
• A total of 182 patients meeting DSM-IV alcohol dependence criteria and 117 controls, both groups being of German descent, were investigated. mGluR7 and mGluR8 polymorphisms were determined using polymerase chain reaction of lymphocyte DNA [9].
• We show a relationship between these three proteins using recombinant PICK1, mGluR7, and PKCalpha, where they were co-immunoprecipitated as a complex from COS-7 cells [10].
• Truncation of the mGluR7 cytoplasmic tail produces a protein that is restricted to a perinuclear intracellular compartment in both neurons and MDCK cells, where this protein colocalizes with a trans-Golgi network antigen [2].
• Thus, AMN082 will be effective for investigating physiological processes related to both mGluR7 activation and internalization such as control of bidirectional plasticity at mossy fiber-st. lucidum interneuron synapses [11].

Associations of GRM7 with chemical compounds

• As described for rat mGluR7, the rank order of agonist potencies is: L-SOP, L-AP4 > L-glutamate > (1S,3R)-ACPD, quisqualate [12].
• LY341495 was less potent at mGlu7 (IC50 = 0.99 microM) and least potent at mGlu4 (IC50 = 22 microM) [13].
• LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM) [14].
• These actions are mediated by PKC-, PKA-, or PKG-dependent phosphorylation of mGluR7 at a single serine residue, Ser(862), in the carboxyl terminus of the receptor [15].

Regulatory relationships of GRM7

• We have previously shown that the interaction of Ca(2+)/calmodulin with the metabotropic glutamate receptor type 7 (mGluR7) promotes the G-protein-mediated inhibition of voltage-sensitive Ca(2+) channels (VSCCs) seen upon agonist activation [16].

Other interactions of GRM7

• Characterization of three novel isoforms of the metabotrobic glutamate receptor 7 (GRM7) [17].
• The nucleotide and amino acid sequences in the coding region of human mGluR4 and mGluR7 were found to be identical to the previously published sequences by Flor et al. and Makoff et al [18].
• The mGluRs form a family of at least seven different subtypes termed mGluR1-mGluR7 [19].
• The genes of two group III metabotropic glutamate receptors, mGluR7 and 8, are candidate susceptibility genes for epilepsy [1].
• The interaction was confirmed in vitro and in vivo by pull-down assays, immunoprecipitation, and colocalization of mGluR7 and MacMARCKS in transfected HEK293 cells and cultured cerebellar granule cells [16].

Analytical, diagnostic and therapeutic context of GRM7

• Northern blot analysis indicate that mGluR7 expression is developmentally regulated [12].
• RT-PCR analysis demonstrated the existence of mGluR7b transcripts in wild-type mouse brain and its absence in mGluR7 knockout mice [12].
• No association found between polymorphisms in genes encoding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study [1].
• Using an immunofluorescence assay we demonstrate that AMN082 induces robust internalization of mGluR7 overexpressed in dissociated hippocampal neurons [11].
• In agreement with mGluR7 in situ hybridisation studies, immunohistochemistry performed at the light microscope level revealed that mGluR7 protein expression occurred most prominently in a particular population of nerve cells common to both the human and rat, located within the cerebellar cortex of gray matter contained within transverse folia [20].

References