title: PKA-mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S-nitrosylation.
abstract: Dexras1 is a small GTPase and plays a central role in neuronal iron trafficking. We have shown that stimulation of glutamate receptors activates neuronal nitric oxide synthase, leading to S-nitrosylation of Dexras1 and a physiological increase in iron uptake. Here we report that Dexras1 is phosphorylated by protein kinase A (PKA) on serine 253, leading to a suppression of iron influx. These effects were directly associated with the levels of S-nitrosylated Dexras1, whereby PKA activation reduced Dexras1 S-nitrosylation in a dose dependent manner. Moreover, we found that adiponectin modulates Dexras1 via PKA. Hence these findings suggest the involvement of the PKA pathway in modulating glutamate-mediated ROS in neurons, and hint to a functional crosstalk between S-nitrosylation and phosphorylation.
authors.affiliation: Department of Psychiatry, and Systems Pharmacology and Translational Therapeutics, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st St. TRL Rm 2207, Philadelphia, PA 19104, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, and Systems Pharmacology and Translational Therapeutics, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st St. TRL Rm 2207, Philadelphia, PA 19104, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Mathias
authors.affiliation: Department of Psychiatry, and Systems Pharmacology and Translational Therapeutics, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st St. TRL Rm 2207, Philadelphia, PA 19104, United States.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Falero-Perez
authors.affiliation: Department of Psychiatry, and Systems Pharmacology and Translational Therapeutics, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31st St. TRL Rm 2207, Philadelphia, PA 19104, United States. Electronic address: sangwonk@mail.med.upenn.edu.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
mesh_terms: D052242:Adiponectin / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D018345:Mice, Knockout; D020125:Mutation, Missense; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; C400132:RASD1 protein, human; D013449:Sulfonamides; D009569:Nitric Oxide; D012694:Serine; D007501:Iron; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Iron; Neuron; Nitric oxide; Phosphorylation; Post-translational modification; S-nitrosylation