Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx.
Internalization of the neurotrophin-Trk receptor complex is critical for many aspects of neurotrophin functions. The mechanisms governing the internalization process are unknown. Here, we report that neuronal activity facilitates the internalization of the receptor for brain-derived neurotrophic factor, TrkB, by potentiating its tyrosine kinase activity. Using three independent approaches, we show that electric stimulation of hippocampal neurons markedly enhances TrkB internalization. Electric stimulation also potentiates TrkB tyrosine kinase activity. The activity-dependent enhancement of TrkB internalization and its tyrosine kinase requires Ca2+ influx through N-methyl-d-aspartate receptors and Ca2+ channels. Inhibition of internalization had no effect on TrkB kinase, but inhibition of TrkB kinase prevents the modulation of TrkB internalization, suggesting a critical role of the tyrosine kinase in the activity-dependent receptor endocytosis. These results demonstrate an activity- and Ca2+-dependent modulation of TrkB tyrosine kinase and its internalization, and they provide new insights into the cell biology of tyrosine kinase receptors.
Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892-4480, USA.
Jing
J
Du
Linyin
L
Feng
Eugene
E
Zaitsev
Hyun-Soo
HS
Je
Xu-Wen
XW
Liu
Bai
B
Lu
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D019921:Biotinylation; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology; D026121:Indole Alkaloids; D007457:Iodine Radioisotopes; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011869:Radioligand Assay; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D016895:Culture Media, Serum-Free; D026121:Indole Alkaloids; D007457:Iodine Radioisotopes; D017475:Receptors, Nerve Growth Factor; C049985:staurosporine aglycone; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB; D002118:Calcium