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The Journal of Neuroscience, August 15, 2002, 22(16):6863-6875

Glycogen Synthase Kinase-3 Is Activated in Neuronal Cells by G₁₂ and G₁₃ by Rho-Independent and Rho-Dependent Mechanisms

C. Laura Sayas, Jesús Avila, and Francisco Wandosell

Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain

Glycogen synthase kinase-3 (GSK-3) was generally considered a constitutively active enzyme, only regulated by inhibition. Here we describe that GSK-3 is activated by lysophosphatidic acid (LPA) during neurite retraction in rat cerebellar granule neurons. GSK-3 activation correlates with an increase in GSK-3 tyrosine phosphorylation. In addition, LPA induces a GSK-3-mediated hyperphosphorylation of the microtubule-associated protein tau. Inhibition of GSK-3 by lithium partially blocks neurite retraction, indicating that GSK-3 activation is important but not essential for the neurite retraction progress. GSK-3 activation by LPA in cerebellar granule neurons is neither downstream of G_i nor downstream of G_q/phospholipase C, suggesting that it is downstream of G_12/13. Overexpression of constitutively active G₁₂ (G₁₂QL) and G₁₃ (G₁₃QL) in Neuro2a cells induces upregulation of GSK-3 activity. Furthermore, overexpression of constitutively active RhoA (RhoAV14) also activates GSK-3 However, the activation of GSK-3 by G₁₃ is blocked by coexpression with C3 transferase, whereas C3 does not block GSK-3 activation by G₁₂. Thus, we demonstrate that GSK-3 is activated by both G₁₂ and G₁₃ in neuronal cells. However, GSK-3 activation by G₁₃ is Rho-mediated, whereas GSK-3 activation by G₁₂ is Rho-independent. The results presented here imply the existence of a previously unknown mechanism of GSK-3 activation by G_12/13 subunits.

Key words: G_12/13; GSK-3 activation; lysophosphatidic acid; neurite retraction; tau hyperphosphorylation; RhoA

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166863-13$05.00/0

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