GM1 GANGLIOSIDE ACTIVATES THE HIGH-AFFINITY NERVE GROWTH-FACTOR RECEPTOR TRKA

The monosialoganglioside GM1 has been shown to possess neurotrophic ac tivity in vitro and in vivo and is now used as an experimental treatme nt for a variety of neurological disorders and trauma. Little is known about the mechanism of action used by GM1. Because GM1 appears to enh ance nerve growth factor (NGF) activity, we have used C6trk(+) cells, a derivative of C6-2B glioma cells that express the high-affinity rece ptor for NGF trkA, to determine whether the neurotrophic effects of GM 1 occurs through induction of trkA activity. Exposure of C6trk(+) cell s to NGF (10-50 ng/ml) resulted in a five- to 10-fold increase in trkA tyrosine phosphorylation within 5 min. Incubation of cells with GM1 r esulted in a threefold increase in trkA phosphorylation beginning with in 1 h and peaking between 3 and 6 h. Optimal responses to GM1 were ob tained using 80-100 mu M concentrations. Moreover, tyrosine phosphoryl ation of known trkA target proteins, such as extracellular signal-regu lated kinases, and sue-associated neurotrophic factor-induced tyrosine -phosphorylated target, were activated upon stimulation of C6trk(+) ce lls with GM1. In addition, GM1 potentiated the NGF-mediated activation of tyrosine phosphorylation of trkA. GM1 failed to induce phosphoryla tion of trkA and target proteins in mock transfected cells. Thus, our data demonstrate that GM1 mimics some of the effects of NGF and sugges t that the neurotrophic properties of GM1 may be attributed to its act ivation of trkA signal transduction.