Two Nedd4-binding Motifs Underlie Modulation of Sodium Channel Nav1.6 by p38 MAPK
Autor: | Xiaoyang Cheng, Stephen G. Waxman, Lynda Tyrrell, Andreas Gasser, Sulayman D. Dib-Hajj, Elaine S. Gilmore |
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Rok vydání: | 2010 |
Předmět: |
Nedd4 Ubiquitin Protein Ligases
Ubiquitin-Protein Ligases media_common.quotation_subject Amino Acid Motifs Nerve Tissue Proteins NEDD4 Hippocampus p38 Mitogen-Activated Protein Kinases Biochemistry Sodium Channels Mice Neurobiology Ubiquitin Animals Humans Phosphorylation Binding site Internalization Molecular Biology media_common Neurons Binding Sites Endosomal Sorting Complexes Required for Transport biology Sodium channel Cell Biology Ubiquitin ligase Cell biology Electrophysiology Mice Inbred C57BL NAV1.6 Voltage-Gated Sodium Channel biology.protein |
Zdroj: | Journal of Biological Chemistry. 285:26149-26161 |
ISSN: | 0021-9258 |
Popis: | Sodium channel Na(v)1.6 is essential for neuronal excitability in central and peripheral nervous systems. Loss-of-function mutations in Na(v)1.6 underlie motor disorders, with homozygous-null mutations causing juvenile lethality. Phosphorylation of Na(v)1.6 by the stress-induced p38 MAPK at a Pro-Gly-Ser(553)-Pro motif in its intracellular loop L1 reduces Na(v)1.6 current density in a dorsal root ganglion-derived cell line, without changing its gating properties. Phosphorylated Pro-Gly-Ser(553)-Pro motif is a putative binding site to Nedd4 ubiquitin ligases, and we hypothesized that Nedd4-like ubiquitin ligases may contribute to channel ubiquitination and internalization. We report here that p38 activation in hippocampal neurons from wild-type mice, but not from Scn8a(medtg) mice that lack Na(v)1.6, reduces tetrodotoxin-S sodium currents, suggesting isoform-specific modulation of Na(v)1.6 by p38 in these neurons. Pharmacological block of endocytosis completely abolishes p38-mediated Na(v)1.6 current reduction, supporting our hypothesis that channel internalization underlies current reduction. We also report that the ubiquitin ligase Nedd4-2 interacts with Na(v)1.6 via a Pro-Ser-Tyr(1945) motif in the C terminus of the channel and reduces Na(v)1.6 current density, and we show that this regulation requires both the Pro-Gly-Ser-Pro motif in L1 and the Pro-Ser-Tyr motif in the C terminus. Similarly, both motifs are necessary for p38-mediated reduction of Na(v)1.6 current, whereas abrogating binding of the ubiquitin ligase Nedd4-2 to the Pro-Ser-Tyr motif results in stress-mediated increase in Na(v)1.6 current density. Thus, phosphorylation of the Pro-Gly-Ser-Pro motif within L1 of Na(v)1.6 is necessary for stress-induced current modulation, with positive or negative regulation depending upon the availability of the C-terminal Pro-Ser-Tyr motif to bind Nedd4-2. |
Databáze: | OpenAIRE |
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