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

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.

Activation of Adenosine A2A Receptors Induces TrkB Translocation and Increases BDNF-Mediated Phospho-TrkB Localization in Lipid Rafts: Implications for Neuromodulation

“…It is also known that most of the activated Trk receptor internalization takes place through clathrin-coated pits (Grimes et al, 1996;Du et al, 2003;Zheng et al, 2008). Although a 30 min incubation with CGS 21680 did not induce TrkB phosphorylation on its own (Fig.…”

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

“…2 D). Surface expression of full-length TrkB in neuronal cells is regulated by neuronal activity and stimulation with BDNF (MeyerFranke et al, 1998;Du et al, 2000;Haapasalo et al, 2002;Du et al, 2003), and in unstimulated cells, most of TrkB.FL is located intracellularly, which might explain the lower amount of TrkB.FL surface staining we observed in HEK 293T cells. Indeed, after permeabilization of cells, staining with an antibody specific for Trk receptors revealed additional intracellular immunoreactivity for AAVFLAGTrkB.FL-infected cells (Fig.…”

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

“…However, we cannot rule out the possibility that antidepressants increase TrkB signaling without influencing BDNF release. Increased intracellular cAMP or membrane depolarization have been shown to increase the membrane localization of TrkB thus enhancing the ability of BDNF to induce TrkB autophosphorylation (Meyer-Franke et al, 1998;Haapasalo et al, 2002;Du et al, 2003;Ji et al, 2005). Furthermore, some G-protein-coupled receptors have been shown to transactivate TrkB receptors independently of BDNF (Lee et al, 2002a;Lee et al, 2002b;Berghuis et al, 2005).…”