Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.

Cohen MR, Johnson WM, Pilat JM, Kiselar J, DeFrancesco-Lisowitz A, Zigmond RE, Moiseenkova-Bell VY
Mol Cell Biol. 2015 35 (24): 4238-52

PMID: 26416880 · PMCID: PMC4648816 · DOI:10.1128/MCB.00549-15

Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

MeSH Terms (21)

Animals Calcium Calcium Channels Cell Line, Tumor Extracellular Signal-Regulated MAP Kinases HEK293 Cells Humans MAP Kinase Signaling System Nerve Growth Factor Neurites Neurogenesis Neurons PC12 Cells Phosphatidylinositol 3-Kinases Phosphorylation rab GTP-Binding Proteins Rats Receptor, trkA RNA, Small Interfering RNA Interference TRPV Cation Channels

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