Intracellular calcium and calmodulin link brain-derived neurotrophic factor to p70S6 kinase phosphorylation and dendritic protein synthesis.
The mammalian target of rapamycin (mTOR)/p70S6 kinase (S6K) pathway plays an important role in brain-derived neurotrophic factor (BDNF)-mediated protein synthesis and neuroplasticity. Although many aspects of neuronal function are regulated by intracellular calcium ([Ca(2+)](i)) and calmodulin (CaM), their functions in BDNF-induced phosphorylation of p70S6K and protein synthesis are largely unknown. Here, we report that BDNF, via TrkB-dependent activation of mTOR, induces sustained phosphorylation of p70S6K at Thr389 and Thr421/Ser424. BDNF-induced phosphorylation at Thr389 was dependent on PI3 kinase but independent of ERK-MAPK. The previously identified MAPK phosphorylation site at Thr421/Ser424 required both PI3K and MAPK in BDNF-stimulated neurons. Furthermore, we found that the reduction in [Ca(2+)](i), but not extracellular calcium, blocked the BDNF-induced phosphorylation of p70S6K at both sites. Inhibition of CaM by W13 also blocked p70S6K phosphorylation. In correlation, W13 inhibited BDNF-induced local dendritic protein synthesis. Interestingly, sustained elevation of [Ca(2+)](i) by membrane depolarization antagonized the BDNF-induced p70S6K phosphorylation. Finally, the BDNF-induced p70S6K phosphorylation did not require the increase of calcium level through either extracellular influx or PLC-mediated intracellular calcium release. Collectively, these results indicate that the basal level of intracellular calcium gates BDNF-induced activation of p70S6K and protein synthesis through CaM. (c) 2009 Wiley-Liss, Inc.
Zhou
Xianju
X
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Lin
David S
DS
Zheng
Fei
F
Sutton
Michael A
MA
Wang
Hongbing
H
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D019208:Brain-Derived Neurotrophic Factor; D002118:Calcium; D002147:Calmodulin; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020813:Receptor, trkB; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases