Alternative splicing of human metabotropic glutamate receptor 3

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
Journal of Neurochemistry (Impact Factor: 4.28). 03/2006; 96(4):1139-48. DOI: 10.1111/j.1471-4159.2005.03609.x
Source: PubMed


The metabotropic glutamate receptor 3 (GRM3, mGluR3) is important in regulating synaptic glutamate. Here, we report the existence of three splice variants of GRM3 in human brain arising from exon skipping events. The transcripts are expressed in prefrontal cortex, hippocampus and cerebellum, and in B lymphoblasts. We found no evidence for alternative splicing of GRM2. The most abundant GRM3 variant lacks exon 4 (GRM3Delta4). In silico translation analysis of GRM3Delta4 predicts a truncated protein with a conserved extracellular ligand binding domain, absence of a seven-transmembrane domain, and a unique 96-amino acid C-terminus. When expressed in rat hippocampal neurons, GRM3Delta4 is translated into a 60 kDa protein. Immunostaining and cell fractionation data indicate that the truncated protein is primarily membrane-associated. An antibody developed against the GRM3Delta4 C-terminus detects a protein of approximately 60 kDa in human brain lysates and in B lymphoblasts, suggesting translation of GRM3Delta4 in vivo. The existence of the GRM3Delta4 isoform is relevant in the light of the reported association of non-coding single nucleotide polymorphisms (SNPs) in GRM3 with schizophrenia, and with the potential of GRM3 as a therapeutic target for several neuropsychiatric disorders.

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Available from: Barbara K Lipska, Oct 17, 2014
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    • "Other isoforms such as mGlu5c, 5d and 5e have been reported in humans (Minakami et al., 1994). Exon-skipping events lead to three spliced variants in mGlu3 (Sartorius et al., 2006). For group III receptors, mGlu4 exists as mGlu4a, and mGlu4b (Thomsen et al., 1997). "
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    • "Moreover, our biochemical analysis suggests that the association with the membrane is strong, consistent with that of a tightly-bound peripheral or integral membrane protein. These results are similar to a recent investigation of the truncated splice variant of the mammalian mGluR3 receptor, which also lacks its 7-TM segment and yet was found to be associated with the plasma membrane [42]. In this case, the authors identified a short hydrophobic segment located at the C-terminal end that was predicted to serve as a single transmembrane domain [42]. "
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    • "The proximity of the GRM1 nsSNP cluster to the exon 6 donor site and exon 7 acceptor site suggest these nsSNPs might perturb the regulatory balance of alternative splicing of this receptor. Consistent with the discovery of GRM1 nsSNP cluster is the discovery of exon skipping in a close homologue of GRM1, GRM3 and its association with schizophrenia [34]. "
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