Constitutive phosphorylation of TrkC receptors in cultured cerebellar granule neurons might be responsible for the inability of NT-3 to increase neuronal survival and to activate p21 ras |
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Authors: | Ute Zirrgiebel Dan Lindholm |
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Institution: | (1) Department of Neurochemistry, Max Planck Institute for Psychiatry, Am Klopferspitz 18a, Martinsried/Munich, Germany |
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Abstract: | The neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are both expressed in developing cerebellum
in addition to their tyrosine kinase receptors, TrkB and TrkC. In contrast to BDNF, NT-3 has only a negligible or a transient
survival activity on cultured cerebellar granule neurons. The granule neurons however, express both TrkC and Trk B receptors
which suggests a basic difference in signaling between BDNF and NT-3 in these neurons. Here we have studied whether this difference
can be attributed to the presence of alternative TrkC receptor variants on the granule neurons and which signaling pathway
is specifically activated by BDNF but not by NT-3 in these neurons. Using RT-PCR it was shown that the cerebellar granule
neurons express the full length TrkC receptor, in addition to variant receptors containing small inserts in the receptor tyrosine
kinase domain. There was no dramatic change in the relative amounts of different TrkC receptors during development. However,
we found the TrkC receptor constitutively phosphorylated even in the absence of added ligand suggesting an interaction of
TrkC with endogenously produced NT-3. In addition, NT-3 was able to phosphorylate the BDNF receptor, TrkB but only at higher
concentration (50 ng/ml). There were also distinct differences in the activation of intracellular molecules by BDNF and NT-3.
Thus, p21 Ras and PLCγ were activated by BDNF but not by NT-3 whereas both BDNF and NT-3 increased calcium and c-fos mRNA
in the granule neurons. These results show that differential activation of specific intracellular pathways such as that of
p21 Ras determines the specific effects of BDNF and NT-3 on granule neuron survival. In addition, since calcium is increased
by NT-3 in the cerebellar granule neurons, this neurotrophin might have some unknown important effects on these neurons.
Special issue dedicated to Dr. Hans Thoenen. |
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Keywords: | NT-3 TrkC granule neuron survival p21 Ras PLC-γ calcium |
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