GM1-induced activation of phosphatidylinositol 3-kinase: involvement of Trk receptors.
The ganglioside GM1 promotes neuronal growth, differentiation, survival, phenotypic expression, and function restoration, by apparently interacting with neurotrophic factors and/or their receptors. In brain, GM1 activates the Trk receptors for neurotrophins and the Raf/MEK/ERK cascade in situ and in vivo. We have expanded these studies and explored whether GM1 recruits the phosphatidylinositol 3 (PI3)-kinase pathway in brain also. Incubating striatal slices with GM1 increased the activity of PI3-kinase in phosphotyrosine immunoprecipitates in a time- and concentration-dependent manner, and the response was blocked by the PI3-kinase inhibitors wortmannin and LY294002. PI3-kinase activation following GM1 was rapid and short lasting with an EC(50) of 5 mumol/L. There was a temporally parallel activation of the downstream PI3-kinase target Akt, which was prevented by PI3-kinase inhibition. PI3-kinase activity was found increased in Trk and Gab1 immunoprecipitates, and co-immunoprecipitation studies demonstrated the association of Trk and Gab1 after GM1 treatment. Enhanced PI3-kinase activity associated with Trk or Gab1 immunoprecipitates was blocked by the Trk inhibitor K252a. GM1 did not appear to transactivate Trk and did not alter the efflux of neurotrophins in striatal slices. Our findings suggest that GM1 induces activation of PI3-kinase that is, in part, mediated through Trk and Gab1.
Duchemin
Anne-Marie
AM
Department of Psychiatry, Division of Molecular Neuropsychopharmacology, College of Medicine, Ohio State University, Columbus, Ohio 43210, USA.
Ren
Qun
Q
Neff
Norton H
NH
Hadjiconstantinou
Maria
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C490896:Gab1 protein, rat; D020933:Neurotrophin 3; D010750:Phosphoproteins; D017475:Receptors, Nerve Growth Factor; D005677:G(M1) Ganglioside; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt