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Neuroscience. 2013 Dec 3;253:214-20. doi: 10.1016/j.neuroscience.2013.08.043. Epub 2013 Aug 30.

PKA modulates iron trafficking in the striatum via small GTPase, Rhes.

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1
Department of Psychiatry and Pharmacology, 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.

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.

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

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