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Two Nedd4-binding motifs underlie modulation of sodium channel Nav1.6 by p38 MAPK

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

Keywords : Amino Acid Motifs,Animals,Binding Sites,Cell Line,cytology,Electrophysiology,Endocytosis,Endosomal Sorting Complexes Required for Transport,Hippocampus,Humans,metabolism,Mice,Mice,Inbred C57BL,Mutation,NAV1.6 Voltage-Gated Sodium Channel,Nedd4 Ubiquitin Protein Ligases,Nerve Tissue Proteins,Nervous System,Neurons,p38 Mitogen-Activated Protein Kinases,Peripheral Nervous System,Phosphorylation,physiology,Sodium Channels,Tetrodotoxin,Ubiquitin-Protein Ligases,, Nedd4binding,Motifs,Underlie,Modulation, trigger point hip pain

Date of Publication : 2010 Aug 20

Authors : Gasser A;Cheng X;Gilmore ES;Tyrrell L;Waxman SG;Dib-Hajj SD;

Organisation : Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

Journal of Publication : J Biol Chem

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/20530479

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