Group‐I metabotropic glutamate receptors, mGlu1a and mGlu5a, 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 activation, down‐regulation of PKCs by phorbol ester treatment for 24 h did attenuate both mGlu1a 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 cell background, these closely related mGlu receptors utilize different G proteins to cause ERK activation and may recruit different tyrosine kinases to facilitate this response.

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