Prevention of apoptotic neuronal death by GM1 ganglioside. Involvement of Trk neurotrophin receptors.
We have used serum-deprived cultures of wild type and genetically modified PC12 cells to investigate the molecular mechanisms by which monosialoganglioside (GM1) rescues neuronal cells from apoptotic death elicited by withdrawal of trophic support. Our findings indicate that GM1-promoted survival can be mediated in part by the Trk NGF receptor as well as by TrkB, and potentially by tyrosine kinase receptors for additional neurotrophic growth factors. Experiments employing K-252a, an inhibitor of Trk kinases, and PC12 cells overexpressing a dominant inhibitory form of Trk both indicate that a portion of the survival-promoting activity of GM1 is evoked by receptor dimerization and autophosphorylation. In consonance with this we find that GM1 stimulates Trk tyrosine autophosphorylation and Trk-associated protein kinase activity. These observations may provide a mechanism to account for the reported in vitro and in vivo trophic actions of GM1.
Ferrari
G
G
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032.
Anderson
B L
BL
Stephens
R M
RM
Kaplan
D R
DR
Greene
L A
LA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D007328:Insulin; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D005677:G(M1) Ganglioside; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB