Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268

Abstract

Metabotropic glutamate receptors 2/3 (mGlu2/3) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu2/3 regulates Akt (protein kinase B) and Wnt (Wingless/Int-1) signaling, two cascades associated with schizophrenia and modified by antipsychotics. Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu 2/3 agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment. LY341495 (mGlu2/3 antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu2/3 complex and Dvl-2 providing a possible mechanism to explain how the mGlu2/3 can mediate changes in Wnt signaling. However, there was no association between the mGlu 2/3 complex and Akt suggesting that changes in Akt signaling following LY341495 and LY379268 treatments may not be directly mediated by the mGlu2/3. Finally, an increase in locomotor activity induced by LY341495 treatment correlated with increased pAkt and pGSK-3 levels and was attenuated by the administration of the GSK-3 inhibitor, SB216763. Overall, the results suggest that mGlu2/3 regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D2 dopamine receptor antagonists (antipsychotic drugs). © 2011 International Society for Neurochemistry.