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PMID: 12177184 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glycogen synthase kinase-3 is activated in neuronal cells by Galpha12 and Galpha13 by Rho-independent and Rho-dependent mechanisms.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 16 ·2002-08-15 ·Pages 6863-75

Sayas CL, Avila J, Wandosell F

Abstract

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 Galpha(i) nor downstream of Galpha(q)/phospholipase C, suggesting that it is downstream of Galpha12/13. Overexpression of constitutively active Galpha12 (Galpha12QL) and Galpha13 (Galpha13QL) 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 Galpha13 is blocked by coexpression with C3 transferase, whereas C3 does not block GSK-3 activation by Galpha12. Thus, we demonstrate that GSK-3 is activated by both Galpha12 and Galpha13 in neuronal cells. However, GSK-3 activation by Galpha13 is Rho-mediated, whereas GSK-3 activation by Galpha12 is Rho-independent. The results presented here imply the existence of a previously unknown mechanism of GSK-3 activation by Galpha12/13 subunits.

MeSH Terms
Animals Calcium-Calmodulin-Dependent Protein Kinases/drug effects,metabolism Cell Differentiation/drug effects,physiology Cell Line Cells, Cultured Cerebellum/cytology,drug effects,metabolism DNA-Binding Proteins/genetics,metabolism Enzyme Activation/drug effects,physiology Enzyme Inhibitors/pharmacology GTP-Binding Protein alpha Subunits, G12-G13 Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Heterotrimeric GTP-Binding Proteins/genetics,metabolism Lysophospholipids/pharmacology Mice Neurites/drug effects,physiology Neuroblastoma/drug therapy,metabolism Neurons/cytology,drug effects,metabolism Nuclear Proteins/biosynthesis Phosphorylation/drug effects Rats Receptors, Cell Surface Receptors, G-Protein-Coupled Receptors, Lysophosphatidic Acid Signal Transduction/drug effects,physiology Transcription Factors/biosynthesis Transfection rhoA GTP-Binding Protein/genetics,metabolism,pharmacology tau Proteins/metabolism
Chemicals
DNA-Binding Proteins Enzyme Inhibitors Lysophospholipids Nuclear Proteins Receptors, Cell Surface Receptors, G-Protein-Coupled Receptors, Lysophosphatidic Acid Transcription Factors tau Proteins Glycogen Synthase Kinases Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3 GTP-Binding Protein alpha Subunits, G12-G13 Heterotrimeric GTP-Binding Proteins rhoA GTP-Binding Protein
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Sayas C Laura
Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
Avila Jesús
Wandosell Francisco
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026701
Published
2002-08-15
Pages
6863-75
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757878
Subset
IM
External Links
PubMed source DOI: 20026701 PMC Full Text View journal details
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