title: PKA modulates iron trafficking in the striatum via small GTPase, Rhes.
abstract: Ras homolog enriched in striatum (Rhes), is a highly conserved small guanosine-5'-triphosphate (GTP) binding protein belonging to the Ras superfamily. Rhes is involved in the dopamine receptor-mediated signaling and behavior though adenylyl cyclase. The striatum-specific GTPase share a close homology with Dexras1, which regulates iron trafficking in the neurons when activated though the post-translational modification called s-nitrosylation by nitric oxide (NO). We report that Rhes physiologically interacted with Peripheral benzodiazepine receptor-associated protein7 and participated in iron uptake via divalent metal transporter 1 similar to Dexras1. Interestingly, Rhes is not S-nitrosylated by NO-treatment, however phosphorylated by protein kinase A at the site of serine-239. Two Rhes mutants - the phosphomimetic form (serine 239 to aspartic acid) and constitutively active form (alanine 173 to valine) - displayed an increase in iron uptake compared to the wild-type Rhes. These findings suggest that Rhes may play a crucial role in striatal iron homeostasis.
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31 St. TRL Rm 2207, Philadelphia, PA 19104.
authors.forename: Bo-Ran
authors.initials: BR
authors.lastname: Choi
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31 St. TRL Rm 2207, Philadelphia, PA 19104.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31 St. TRL Rm 2207, Philadelphia, PA 19104.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31 St. TRL Rm 2207, Philadelphia, PA 19104.
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Cheah
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perlman School of Medicine at the University of Pennsylvania, 125 S 31 St. TRL Rm 2207, Philadelphia, PA 19104.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D027682:Cation Transport Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D014162:Transfection; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D027682:Cation Transport Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D003676:Deferoxamine; D005290:Ferric Compounds; D019204:GTP-Binding Proteins; D005982:Glutathione Transferase; D049452:Green Fluorescent Proteins; D007501:Iron; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D000644:Quaternary Ammonium Compounds; D012694:Serine; D017262:Siderophores; D000099236:Solute Carrier Family 11, Member 2; C449459:ACBD3 protein, human; C486702:RASD2 protein, human; C013531:ferric ammonium citrate
keywords: A173V; DMT1; EDTA; G protein; G31V; GEF; GST; GTP; HRP; IRE; NTBI; PAP7; PBS; PKA; Rhes; S239A; S239D; Tf; TfR; alanine-173 valine; divalent metal transporter 1; ethylenediaminetetraacetic acid; glutathione S-transferase; glycine-31 valine; guanidine exchange factor; guanosine-5′-triphosphate; horseradish peroxidase; iron uptake; iron-responsive element; nNOS; neuronal nitric oxide synthase, NO, nitric oxide; non-transferrin-bound iron; peripheral benzodiazepine receptor-associated protein7; phosphate-buffered saline; phosphorylation; protein kinase A; ras homolog enriched in striatum; serine-239 alanine; serine-239 aspartic acid; striatum; transferrin; transferrin receptor; λ PPase; λ phosphatase