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J. Cell Biol. 163 (2): 385-395

Copyright © 2003 by the Rockefeller University Press.


Article

Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx

Jing Du1,2, Linyin Feng1,3, Eugene Zaitsev1, Hyun-Soo Je1,4, Xu-wen Liu1, and Bai Lu1

1 Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892
2 Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorder Program, National Institute of Mental Health, NIH, Bethesda, MD 20878
3 Institutes of Neuroscience, Chinese Academy of Sciences, Shanghai, China 200031
4 Genetics Graduate Program, George Washington University, Washington, DC 20052

Address correspondence to Bai Lu, Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, NICHD, NIH Building 49, Rm. 6A80, 49 Convent Dr., Bethesda, MD 20892-4480. Tel.: (301) 435-2970. Fax: (301) 496-1777. email: bailu{at}mail.nih.gov

Abstract: 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.

Key Words: BDNF; endocytosis; calcium influx; hippocampus; activity dependent


Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; CNQX, 6-cyano-7-nitroquinozaline-2,3-dione; Kyn, kynurenic acid; MDC, monodansylcadavenrine; NMDA, N-methyl-D-aspartate; p75NR, p75 NGF receptors; TBS, theta burst stimulation; TTX, tetrodotoxin.


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