Abstract
Neurotrophins activate Trk receptor signaling to support neuronal survival and many aspects of neuronal function. Early studies demonstrated that TrkA formed a complex with the p75 neurotrophin receptor (p75NTR), which increased the affinity and selectivity of NGF binding, however, whether interaction of p75NTR with other Trk receptors performs a similar function to enhance ligand binding has not been demonstrated. We investigated the interaction of TrkB with full length p75NTR in hippocampal neurons in response to BDNF and found that the association of these receptors occurs after ligand binding and requires phosphorylation of TrkB, indicating that formation of this receptor complex was not necessary for ligand binding. Moreover, the interaction of these receptors required internalization and localization to early endosomes. We found that association of TrkB with p75NTR was necessary for optimal downstream signaling of the PI3K-Akt pathway, but not the Erk pathway, in hippocampal neurons. The absence of p75NTR impaired the ability of BDNF to rescue hippocampal neurons in a trophic deprivation model, suggesting that p75NTR facilitates the ability of TrkB to activate specific pathways to promote neuronal survival.
Highlights
The neurotrophin family of trophic factors, which includes NGF, BDNF, NT3, and NT4, regulate multiple aspects of neuronal survival and function by interacting with distinct receptor complexes
Previous studies had shown that p75 neurotrophin receptor (p75NTR) interacts preferentially with the phosphorylated form of TrkB (Bibel et al, 1999), which we confirmed, suggesting that the association of the two receptors occurs after TrkB is activated and not required for binding of the ligand
A previous study showed that endocytosis was necessary for TrkA or TrkB-induced activation of Akt, but not Erk (Zheng et al, 2008)
Summary
The neurotrophin family of trophic factors, which includes NGF, BDNF, NT3, and NT4, regulate multiple aspects of neuronal survival and function by interacting with distinct receptor complexes. These factors promote survival, axonal growth, and synaptic activity by signaling via Trk receptors, and can induce apoptosis by signaling via the p75 neurotrophin receptor (p75NTR). The association of p75NTR with a member of the sortilin family allows the binding of proneurotrophins and apoptotic signaling by p75NTR (Lee et al, 2001; Volosin et al, 2006) Once receptors bind their ligands, receptor internalization and trafficking are important aspects of their signaling. TrkB receptors at the synapse can promote glutamatergic signaling and modulate synaptic activity (Schinder and Poo, 2000) while TrkB receptors in dendrites can promote BDNF-induced branching (Lazo et al, 2013)
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