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Differential effects of BDNF and neurotrophin 4 ( NT 4) on endocytic sorting of TrkB receptors
Author(s) -
Proenca Catia C.,
Song Minseok,
Lee Francis S.
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13676
Subject(s) - tropomyosin receptor kinase b , neurotrophin , tropomyosin receptor kinase a , neurotrophic factors , brain derived neurotrophic factor , microbiology and biotechnology , low affinity nerve growth factor receptor , receptor , biology , endocytic cycle , chemistry , neuroscience , biochemistry , endocytosis
Neurotrophins are a family of growth factors playing key roles in the survival, development, and function of neurons. The neurotrophins brain‐derived neurotrophic factor ( BDNF ) and NT 4 both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. The molecular mechanism of how TrkB activation by BDNF and NT 4 leads to diverse outcomes is unknown. Here, we report that BDNF and NT 4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions in cultured cortical neurons. Fluorescent microscopy and surface biotinylation experiments showed that both neurotrophins stimulate internalization of TrkB with similar kinetics. Exposure to BDNF for 2–3 h reduced the surface pool of TrkB receptors to half, whereas a longer treatment (4–5 h) with NT 4 was necessary to achieve a similar level of down‐regulation. Although BDNF and NT 4 induced TrkB phosphorylation with similar intensities, BDNF induced more rapid ubiquitination and degradation of TrkB than NT 4. Interestingly, TrkB receptor ubiquitination by these ligands have substantially different pH sensitivities, resulting in varying degrees of receptor ubiquitination at lower pH levels. Consequently, NT 4 was capable of maintaining longer sustained downstream signaling activation that correlated with reduced TrkB ubiquitination at endosomal pH . Thus, by leading to altered endocytic trafficking itineraries for TrkB receptors, BDNF and NT 4 elicit differential TrkB signaling in terms of duration, intensity, and specificity, which may contribute to their functional differences in vivo .The neurotrophins, brain‐derived neurotrophic factor ( BDNF ) and neurotrophin‐4 ( NT 4), both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. Here, we propose that BDNF and NT 4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions. BDNF induces more rapid ubiquitination and degradation of TrkB than NT 4. Consequently, NT 4 is capable of maintaining more sustained signaling downstream of TrkB receptors.