Group-I metabotropic glutamate receptors, mG1u1a and mG1u5a, couple to extracellular signal-regulated kinase (ERK) activation via distinct, but overlapping, signalling pathways

The coupling of the group I metabotropic glutamate receptors, mGlu1a and mGlu5a, to the extracellular signal-regulated protein kinase (ERK) pathway has been studied in Chinese hamster ovary cell-lines where receptor expression is under inducible control. Both mGlu receptors stimulated comparable, robust,and agonist concentration-dependent ERK activations in the CHO cell-lines. The mGlu1a receptor-mediated ERK response was almost completely attenuated by pertussis toxin (PTx) pretreatment, whereas the mGlu5a-ERK response, and the phosphoinositide response to activation of either receptor, was PTx-insensitive. mGlu1a and mGlu5a receptor coupling to ERK occurred via mechanisms independent of phosphoinositide 3-kinase activity and intracellular and/or extracellular Ca2+ concentration. While acute treatment with a protein kinase C (PKC) inhibitor did not attenuate agonist-stimulated. ERK activaition, Own-regulation of PKCS by phorbol ester treatment for 24 h did attenuate both mGlu5a and mGlu5a receptor-mediated responses. Further, inhibition of Src non-receptor tyrosine kinase activity by, PP1 attenuated the ERK response generated by both receptor subtypes, but only mGlu1a receptor-ERK activation was attenuated, by PDGF receptor tyrosine kinase inhibitor AG1296. These findings demonstrate that, although expressed in a common call background, these closely related mGlu receptors utilize different G proteins to cause ERK activation and may recruit different tyrosine kinases to facilitate this response.