N-desmethylclozapine, a major clozapine metabolite, regulates glycogen synthase 3-β through stimulation of ð opioid receptors and PI3 kìnase/AKt pathway.
OLIANAS, MARIA CONCETTA;DEDONI, SIMONA;ONALI, PIER LUIGI
2007-01-01
Abstract
The serine/threonine protein kinase glycogen synthase kinase-3 (GSK-3) has recently been identified as one of the key targets of mood stabilizing agents and antipsychotic drugs. These drugs have been found to promote the phosphorylation at serine 9 (Ser9) and the consequent inactivation of GSK-3β, thereby inhibiting GSK-dependent intracellular signaling. We have previously shown that N-desmethylclozapine (NDMC), a major metabolite of the atypical antipsychotic clozapine, is a potent and efficacious ð opioid receptor agonist. In the present study, we investigated whether NDMC regulates GSK-3β phosphorylation by acting at δ opioid receptor (DOR). We found that in Chinese hamster ovary cells transfected whith the human DOR and in NG108-15 neuroblastoma x glioma hybrid cells expressing endogenous DOR NDMC induced a rapid phosphorylation of GSK-3β at Ser9. This effect was mimicked by the δ opioid receptor ogonist DPDPE and was blocked by naloxone. In addition, in both cell systems NDMC and DPDPE induced the phosphorylation of the protein kinase Akt-1. Pretreatment of cells with the phosphatidylinositol 3 kinase (PI3K) inhibitor worthmannin markedly reduced the stimulatory effect of NDMC on GSK-3β and Akt-1 phosphorylation. These data indicate that NDMC can regulate GSK-dependent signaling by stimulating δ opioid receptors coupled to the PI3K/AKt pathway and suggest that this property may contribute to the antidepressant and atypical antipsychotic activity of clozapine.Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.