title: Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Cohen
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pilat
authors.affiliation: Center for Proteomics and Bioinformatics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Janna
authors.initials: J
authors.lastname: Kiselar
authors.affiliation: Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: DeFrancesco-Lisowitz
authors.affiliation: Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Zigmond
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA vxm102@case.edu.
authors.forename: Vera Y
authors.initials: VY
authors.lastname: Moiseenkova-Bell
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D020932:Nerve Growth Factor / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D015220:Calcium Channels; C502240:NGF protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C400769:TRPV2 protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716466:rab7 GTP-binding proteins, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases; D020691:rab GTP-Binding Proteins; D002118:Calcium