title: GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain.
abstract: We investigated the ability of GM1 to induce phosphorylation of the tyrosine kinase receptor for neurotrophins, Trk, in rat brain, and activation of possible down-stream signaling cascades. GM1 increased phosphorylated Trk (pTrk) in slices of striatum, hippocampus and frontal cortex in a concentration- and time-dependent manner, and enhanced the activity of Trk kinase resulting in receptor autophosphorylation. The ability of GM1 to induce pTrk was shared by other gangliosides, and was blocked by the selective Trk kinase inhibitors K252a and AG879. GM1 induced phosphorylation of TrkA > TrkC > TrkB in a region-specific distribution. Adding GM1 to brain slices activated extracellular-regulated protein kinases (Erks) in all three brain regions studied. In striatum, GM1 elicited activation of Erk2 > Erk1 in a time-and concentration-dependent manner. The GM1 effect on Erk2 was mimicked by other gangliosides, and was blocked by the Trk kinase inhibitors K252a and AG879. Pertussis toxin, as well as Src protein tyrosine kinase and protein kinase C inhibitors, did not prevent the GM1-induced activation of Erk2, apparently excluding the participation of Gi and Gq/11 protein-coupled receptors. Intracerebroventricular administration of GM1 induced a transient phosphorylation of TrkA and Erk1/2 in the striatum and hippocampus complementing the in situ studies. These observations support a role for GM1 in modulating Trk and Erk phosphorylation and activity in brain.
authors.affiliation: Department of Psychiatry, The Ohio State University College of Medicine and Public Health, 1670 Upham Drive, Columbus, OH 43210, USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Duchemin
authors.forename: Qun
authors.initials: Q
authors.lastname: Ren
authors.forename: Lili
authors.initials: L
authors.lastname: Mo
authors.forename: Norton H
authors.initials: NH
authors.lastname: Neff
authors.forename: Maria
authors.initials: M
authors.lastname: Hadjiconstantinou
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000008:administration & dosage / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005732:Gangliosides / Q000494:pharmacology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D005732:Gangliosides; D011956:Receptors, Cell Surface; D005677:G(M1) Ganglioside; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins