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

Abstract

Metabotropic glutamate receptors 2/3 (mGlu(2/3)) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu(2/3) 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 (mGlu(2/3) antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu(2/3) complex and Dvl-2 providing a possible mechanism to explain how the mGlu(2/3) 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 mGlu(2/3) . 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 mGlu(2/3) regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D(2) dopamine receptor antagonists (antipsychotic drugs).

• Authors: Laurie P Sutton, Walter J Rushlow
• Journal: Journal of neurochemistry (J Neurochem) Vol. 117 Issue 6 Pg. 973-83 (Jun 2011) ISSN: 1471-4159 [Electronic] England
• PMID: 21477044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Chemical References

• Amino Acids
• Bridged Bicyclo Compounds, Heterocyclic
• LY 341495
• LY 379268
• Receptors, Metabotropic Glutamate
• Wnt Proteins
• Xanthenes
• metabotropic glutamate receptor 2
• metabotropic glutamate receptor 3
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Amino Acids (pharmacology)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Corpus Striatum (drug effects, physiology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Male
• Motor Activity (drug effects)
• Prefrontal Cortex (drug effects, physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (agonists, antagonists & inhibitors)
• Signal Transduction
• Wnt Proteins (physiology)
• Xanthenes (pharmacology)