title: Diminished iron concentrations increase adenosine A(2A) receptor levels in mouse striatum and cultured human neuroblastoma cells.
abstract: Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D(2) receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A(2A) (A(2A)R) but not A(1) receptor (A(1)R) compared to mice on a normal diet. Between two inbred murine strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A(2A)R density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A(2A)R. In these cells, A(2A)R agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A(2A)R. A significant correlation (r(2)=0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A(2A)R protein density. In conclusion, the A(2A)R is increased across different iron-insufficient conditions. The relation between A(2A)R and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.
authors.affiliation: Neurology Department, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Gulyani
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Earley
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mughal
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
authors.forename: Marc
authors.initials: M
authors.lastname: Gleichmann
authors.forename: Byron C
authors.initials: BC
authors.lastname: Jones
authors.forename: Richard P
authors.initials: RP
authors.lastname: Allen
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000090463:Iron Deficiencies; D019266:Iron, Dietary / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009447:Neuroblastoma / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D019266:Iron, Dietary; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; D011990:Receptors, Transferrin; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000242:Cyclic AMP; D003676:Deferoxamine; D000241:Adenosine