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GM 1 ganglioside enhances Ret signaling in striatum
Author(s) -
Newburn Erin N.,
Duchemin AnneMarie,
Neff Norton H.,
Hadjiconstantinou Maria
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12760
Subject(s) - glial cell line derived neurotrophic factor , gdnf family of ligands , neurotrophic factors , proto oncogene proteins c ret , neurotrophin , phosphorylation , receptor tyrosine kinase , microbiology and biotechnology , biology , proto oncogene tyrosine protein kinase src , protein kinase b , tyrosine kinase , striatum , dopaminergic , brain derived neurotrophic factor , chemistry , signal transduction , receptor , endocrinology , dopamine , biochemistry
It has been proposed that GM 1 ganglioside promotes neuronal growth, phenotypic expression, and survival by modulating tyrosine kinase receptors for neurotrophic factors. Our studies tested the hypothesis that GM 1 exerts its neurotrophic action on dopaminergic neurons, in part, by interacting with the GDNF (glia cell‐derived neurotrophic factor) receptor complex, Ret tyrosine kinase and GFR α1 co‐receptor. GM 1 addition to striatal slices in situ increased Ret activity in a concentration‐ and time‐dependent manner. GM 1‐induced Ret activation required the whole GM 1 molecule and was inhibited by the kinase inhibitors PP 2 and PP 1. Ret activation was followed by Tyr1062 phosphorylation and PI 3 kinase/Akt recruitment. The Src kinase was associated with Ret and GM 1 enhanced its phosphorylation. GM 1 responses required the presence of GFR α1, and there was a GM 1 concentration‐dependent increase in the binding of endogenous GDNF which paralleled that of Ret activation. Neutralization of the released GDNF did not influence the Ret response to GM 1, and GM 1 had no effect on GDNF release. Our in situ studies suggest that GM 1 via GFR α1 modulates Ret activation and phosphorylation in the striatum and provide a putative mechanism for its effects on dopaminergic neurons. Indeed, chronic GM 1 treatment enhanced Ret activity and phosphorylation in the striatum of the MPTP ‐mouse and kinase activation was associated with recovery of dopamine and DOPAC deficits.It has been proposed that the ganglioside GM1 promotes neuronal growth, phenotypic expression, and survival by modulating tyrosine kinase receptors for neurotrophic factors. We provide evidence that the GM1 enhances the activity of Ret tyrosine kinase receptor for glia cell‐derived neurotrophic factor (GDNF) in the striatum in situ and in vivo , and propose that this might be a mechanism for GM1's neurotrophic actions on dopaminergic neurons. Ret activation is followed by Tyr1062 and Tyr981 phosphorylation and recruitment of PI3‐K/Akt, Erk, and Src signaling. GM1 apparently acts by increasing the binding of endogenous GDNF to GFRα1 co‐receptor, which is required for the GM1 effect on Ret.