Characterization of TrkB receptor-mediated signaling pathways in rat cerebellar granule neurons: involvement of protein kinase C in neuronal survival.
TrkB belongs to the Trk family of tyrosine kinase receptors and mediates the response to brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5). Here, we report that both truncated and full-length forms of TrkB receptors are expressed in developing cerebellar granule neurons. BDNF and NT-4/5 increased the survival of cultured cerebellar granule neurons. BDNF and NT-4/5 also induced an autophosphorylation of TrkB receptors and subsequently resulted in a phosphorylation and binding of phospholipase C-gamma (PLC-gamma) and SH2-containing sequence to the autophosphorylated TrkB receptors. Both contain src homology 2 (SH2) regions. In keeping with a signaling function of PLC-gamma, BDNF increased the phosphatidylinositol (PI) turnover and elevated intracellular calcium levels. To investigate the involvement of protein kinase C (PKC) in the survival of granular neurons, we show here activation of PKC after BDNF or TPA treatment and blocking of the observed survival-promoting effects of BDNF and TPA with calphostin C, a specific PKC inhibitor. In addition, BDNF activated c-ras in a concentration-dependent manner. These results suggest that two different pathways, the c-ras and the PLC-gamma pathway, are activated by TrkB receptors in primary neurons and that PKC activation is involved in the survival promoting effect of BDNF.
Zirrgiebel
U
U
Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Munich, Germany.
Ohga
Y
Y
Carter
B
B
Berninger
B
B
Inagaki
N
N
Thoenen
H
H
Lindholm
D
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D011905:Genes, ras; D007527:Isoenzymes / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000494:pharmacology; D018909:src Homology Domains / Q000502:physiology
D007527:Isoenzymes; D009414:Nerve Growth Factors; D010716:Phosphatidylinositols; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D011493:Protein Kinase C; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium