title: Prostaglandin E2 promotes Na1.8 trafficking via its intracellular RRR motif through the protein kinase A pathway.
abstract: Voltage-gated sodium channels (Na(v)) are essential for the initiation and propagation of action potentials in neurons. Na(v)1.8 activity is regulated by prostaglandin E(2) (PGE(2)). There is, however, no direct evidence showing the regulated trafficking of Na(v)1.8, and the molecular and cellular mechanism of PGE(2)-induced sodium channel trafficking is not clear. Here, we report that PGE(2) regulates the trafficking of Na(v)1.8 through the protein kinase A (PKA) signaling pathway, and an RRR motif in the first intracellular loop of Na(v)1.8 mediates this effect. In rat dorsal root ganglion (DRG) neurons, prolonged PGE(2) treatment enhanced Na(v)1.8 currents by increasing the channel density on the cell surface. Activation of PKA by forskolin had the same effect on DRG neurons and human embryonic kidney 293T cells expressing Na(v)1.8. Inhibition of PKA completely blocked the PGE(2)-promoted effect on Na(v)1.8. Mutation of five PKA phosphorylation sites or the RRR motif in the first intracellular loop of Na(v)1.8 abolished the PKA-promoted Na(v)1.8 surface expression. Furthermore, a membrane-tethered peptide containing the intracellular RRR motif disrupted the PGE(2)-induced promotion of the Na(v)1.8 current in DRG neurons. Our data indicate that PGE(2) promotes the surface expression of Na(v)1.8 via an intracellular RRR motif, and provide a novel mechanism for functional modulation of Na(v)1.8 by hyperalgesic agents.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Su
authors.forename: Lan
authors.initials: L
authors.lastname: Bao
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D018929:Cell Culture Techniques; D005576:Colforsin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; D015222:Sodium Channels; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone