Differential roles of mGluR2 and mGluR3 in the brain
Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are negatively coupled to adenylate cyclase and cAMP transduction system. They decrease cAMP through a pertussis toxin-sensitive Gprotein coupled mechanism. Recently we have shown that mGluR3 expressed in rat cerebellar granule cells and astrocytes also may be coupled through a G-protein mechanism to a cGMP transduction pathway. To test the hypothesis that mGluR2 and mGluR3 share a coupling to the cGMP pathway, their cDNA were transfected into C6 glioma cells, characterized by robust cGMP response, and their coupling to cAMP and cGMP transduction pathways was characterized. Consistent with data from neurons and astrocytes, mGluR3 stably expressed in C6 cells responded to agonists with reductions in cGMP levels. In contrast, the mGluR2 receptor was negatively coupled to cAMP in C6 cells but not to cGMP, indicating the functional difference between these two receptors. The coupling to cGMP signal transduction depends on the cell type – it is pertussis toxin-sensitive in the astrocytes and C6 mGluR3 cell line, while it is not in the cerebellar granule cells. In all investigated cell types the coupling was not mediated by the interactions with phosphodiesterase (IBMX-insensitive). Evidence that human mGluR3 (GRM3 gene) may be a susceptibility gene for schizophrenia and prospective therapeutic potential of group II agonists may speed up the development of selective agonists or positive allosteric modulators for these two receptors.