Inhibition of microtubule formation by metabotropic glutamate receptors.
Activation of glutamate receptors is known to alter the biophysical state of the cytoskeleton of neurons in the developing brain. In this study, we examined the ability of G protein-coupled metabotropic glutamate receptors (mGluRs) to inhibit the formation of processes induced by the expression of the microtubule-associated protein MAP2c. The infection of insect MG-1 cells with a recombinant baculovirus (BV) encoding MAP2c induced the formation of fine filamentous processes. The binding of MAPs to tubulin promotes tubulin polymerization and the formation of microtubules. Co-infection with BVs for the phosphoinositide (PI)-linked mGluR1a or mGluR1b receptor subtypes inhibited the formation of processes induced by MAP2c, whereas co-infection with BVs encoding the mGluR4a or mGluR4b subtypes that couple to adenylyl cyclase did not inhibit the formation of processes. The biochemical pathways responsible for producing the inhibitory effect of mGluR1 were investigated. Inhibitors of protein kinase C, calcium/calmodulin-dependent kinase, and protein tyrosine kinases did not block the inhibitory effect of mGluR1a. The calcium chelator BAPTA and the calcium depletor thapsigargin also did not affect the ability of mGluR1a to inhibit process formation. In contrast, inhibitors of phospholipase C reversed the effect of mGluR1 on process formation, suggesting that one or more metabolites in the PI pathway were responsible for the inhibitory effect. These findings indicate that PIs generated by activation of mGluRs inhibit the binding of MAPs to tubulin and reduce tubulin polymerization and microtubule stability.
Huang
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Faculty of Pharmacy and Department of Pharmacology, University of Toronto, Ontario, Canada.
Hampson
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D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000502:physiology; D008870:Microtubules / Q000502:physiology*; D009036:Moths; D010716:Phosphatidylinositols / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C104077:metabotropic glutamate receptor type 1; D010738:Type C Phospholipases