Unraveling Internalization Signals

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Science's STKE  04 Nov 2003:
Vol. 2003, Issue 207, pp. tw429-TW429
DOI: 10.1126/stke.2003.207.tw429

Du et al. investigated the possibility that neuronal activity could influence internalization of neurotrophin-receptor complexes, a process required for some aspects of neurotrophin signaling, and discovered an unexpected link between calcium, receptor tyrosine kinase activity, and brain-derived neurotrophic factor (BDNF)-TrkB receptor complex internalization. Neuronal activity can promote the efficacy with which BDNF affects neuronal survival, synaptic efficacy, and synaptic plasticity, which provides a possible mechanism for selective activity-dependent enhancement of particular neuronal pathways. Du et al. used fluorescent imaging of biotinylated BDNF, quantification of radiolabeled BDNF on cell surface and the amount internalized, and Western analysis of TrkB in combination with electrical field stimulation to show that stimulus protocols associated with production of long-term potentiation promoted internalization of BDNF and TrkB in cultured hippocampal neurons. The authors used electrical stimulation of cells undergoing pharmacological blockade of voltage-dependent calcium channels or N-methyl-D-aspartate receptors, or in medium made without calcium, to show that activity-dependent internalization of BDNF and TrkB depended on calcium influx. BDNF stimulated tyrosine phosphorylation of TrkB, and electrical stimulation enhanced BDNF-dependent TrkB phosphorylation, an enhancement that depended on calcium influx. Pharmacological blockade of BDNF-dependent TrkB internalization did not affect activity-dependent enhancement of TrkB phosphorylation, whereas inhibition of TrkB kinase activity, either pharmacologically or with a dominant-negative TrkB mutant, blocked receptor internalization. Thus, neuronal activity appears to enhance BDNF-TrkB internalization through calcium-dependent stimulation of TrkB tyrosine phosphorylation.

J. Du, L. Feng, E. Zaitsev, H.-S. Je, X.-W. Liu, B. Lu, Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx. J. Cell Biol. 163, 385-395 (2003). [Abstract] [Full Text]

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