Group-I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to extracellular signal-regulated kinase (ERK) activation via distinct, but overlapping, signalling pathways

J Neurochem. 2002 Dec;83(5):1139-53. doi: 10.1046/j.1471-4159.2002.01217.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Cricetinae
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Activators / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Female
  • Humans
  • Hydrolysis / drug effects
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Ovary / cytology
  • Ovary / drug effects
  • Ovary / metabolism
  • Pertussis Toxin / pharmacology
  • Phosphatidylinositols / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Quisqualic Acid / pharmacology
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • src-Family Kinases / antagonists & inhibitors


  • Enzyme Activators
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Quisqualic Acid
  • Pertussis Toxin
  • Receptors, Platelet-Derived Growth Factor
  • src-Family Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Calcium