Disease relevance of GRM4

• Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders [1].
• In addition, 241 cases of colorectal carcinomas were examined and correlations between mGluR4 expression and various clinicopathologic parameters were then statistically analyzed [2].
• Recently, we reported that mGluR4 mediates 5-fluorouracil resistance in a human colon cancer cell line [2].
• In the corresponding malignant tissues, mGluR4 expression was frequently identified in colorectal carcinoma (68%), followed by malignant melanoma, laryngeal carcinoma, and breast carcinomas [2].
• Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions [3].

Psychiatry related information on GRM4

• Results of our studies indicate that a combined administration positive allosteric modulation of mGlu4 receptor and agonists of group III mGlu receptors may be a promising target in the future treatment of depressive disorder [4].

High impact information on GRM4

• As mGluR4 represents an inhibitory class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expression of mGluR4 in surgical hippocampal specimens obtained from patients with TLE by using immunohistochemistry and in situ hybridization [5].
• Although the hippocampi of control specimens (n = 11) were almost devoid of mGluR4 immunolabeling, all TLE specimens (n = 35) showed a striking up-regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus [5].
• In particular, the mutations K74Y and K317R induced dramatic triple-order-of-magnitude increases in the affinity of ibotenic acid at mGluR4, making the affinity equivalent to that of mGluR1 [6].
• Indeed, the mGlu2 and mGlu4 and -8 receptors can discriminate between alpha subunits that differ at the level of their C-terminal end only (such as Gqo and Gqz) [7].
• To that aim, we analyzed the coupling properties of mGlu2 and mGlu4 or -8 receptors and chimeras containing the i2 loop of the converse receptor to G-protein alpha subunits that only differ by their C termini (Gqo,Gqz, and their point mutants) [7].

Biological context of GRM4

• Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping [8].
• Our approach has been to increase the affinity of the classic mGluR1 agonists, quisqualic acid and ibotenic acid, at mGluR4 by making various point mutations that mimicked mGluR1 residues [6].
• LY341495 was less potent at mGlu7 (IC50 = 0.99 microM) and least potent at mGlu4 (IC50 = 22 microM) [9].
• Complementary DNAs (cDNAs) encoding the human mGluR4, human mGluR7, and human mGluR8 were isolated from human cerebellum, fetal brain or retinal cDNA libraries [10].
• 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 [10].

Anatomical context of GRM4

• Furthermore, novel expression of metabotropic glutamate receptor 1 (mGluR1), mGluR4, and mGluR5 by human brain and dermal microvascular endothelial cells was demonstrated by reverse transcription-PCR, in situ hybridization, immunofluorescence, and Western blot analysis [11].
• Correspondingly, in situ hybridization experiments showed only expression of mGluR1 (group I) and mGluR4 and 7 (group III) in human motor neurons [12].
• Expression of mGluR4 was detected in 131 (54%) of 241 colorectal carcinomas and 12 (5%) cases among them showed overexpression in their cytoplasms [2].
• RESULTS: Expression of mGluR4 was identified in the normal epithelia of the upper respiratory tract, gastrointestinal tracts, breast, uterine cervix, urinary bladder, and skin, whereas it was not detected in the thyroid, lung alveoli, liver, testis, or prostate [2].
• In this study, we evaluated the nonneural expression of mGluR4 and clarified the existence of mGluR4 in normal colon epithelium and colorectal carcinomas [2].

Associations of GRM4 with chemical compounds

• Furthermore, the affinity of quisqualic acid at mGluR4 was increased to the same level as mGluR1 by the two double mutations, K74Y/K317R and K74Y/E287G [6].
• LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM) [13].
• The subtypes of group 2 (mGluR2 and 3) and group 3 (mGluR4, 6 7 and 8) inhibit adenylate cyclase and, thereby, mediate a decrease in cAMP concentration [14].
• Transfection of GqGi3 into previously validated stable CHO cell lines expressing mGluR2 or mGluR4 allowed for the selection of new double transfectants in which application of L-glutamate and other mGluR agonists resulted in calcium coupling with a high signal:noise ratio (maximal changes in relative fluorescence units up to 20,000) [15].
• To get an insight into the bioactive conformation of glutamic acid and its topological environment at the mGluR4 binding site, a pharmacophore model was constructed using molecular modeling [16].

Other interactions of GRM4

• Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar KB value for mGluR2 and mGluR4 [17].
• We sequenced between 1865 (mGluR8a) and 3697 (mGluR1) total nucleotides for each macaque gene and obtained complete coding sequences for GluR1-7, mGluR3 and mGluR4 [18].
• Signals for mGluR1 and mGluR5 were enriched in the dorsal horn, while mGluR4 mRNA was abundant in the ventral horn [19].
• We report that mGluR2 and mGluR4, two receptors negatively coupled to adenylyl cyclase, activate PLC when coexpressed with G alpha 15, G alpha ql or G alpha qo [17].
• A comparison with the corresponding human sequences reveal that the coding region of macaque GluR6 demonstrates the highest homology with only 26 nucleotide substitutions (99% homology), while mGluR4 demonstrates the lowest with 68 substitutions (97.5%) [18].

Analytical, diagnostic and therapeutic context of GRM4

• In this study, we explored the ligand binding pocket of the Group III mGluR4 receptor subtype using site-directed mutagenesis and radioligand binding [20].
• EXPERIMENTAL DESIGN: mGluR4 expression was investigated in 21 normal and 312 malignant tissues from various organs using immunohistochemistry [2].
• Loss of mGluR4 expression was negatively associated with tumor differentiation (P = 0.028), whereas overexpression of mGluR4 was positively associated with recurrence (P = 0.034) and poor disease-free survival (P = 0.017) in multivariate analyses [2].
• In Northern blots mGluR4 mRNA appears to be brain-specific, and shows a distinct distribution (excluding the cerebellum), being expressed in the thalamus, hypothalamus and caudate nucleus [21].
• Truncation of the ATDs of mGluR4 and mGluR8 40 amino acids upstream of the first transmembrane domain produced soluble proteins that were secreted into the cell culture media of transfected human embryonic kidney cells [22].

References