Diminished iron concentrations increase adenosine A2A receptor levels in mouse striatum and cultured human neuroblastoma cells

• Published in: Experimental neurology 2009-02, Vol.215 (2), p.236-242
• Main Authors: GULYANI, Seema, EARLEY, Christopher J, ALIEN, Richard P, MATTSON, Mark P, CAMANDOLA, Simonetta, MAUDSLEY, Stuart, FERRE, Sergi, MUGHAL, Mohamed R, MARTIN, Bronwen, CHENG, Aiwu, GLEICHMANN, Marc, JONES, Byron C
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Development. Senescence. Regeneration. Transplantation; Fundamental and applied biological sciences. Psychology; Medical sciences; Neurology; Vertebrates: nervous system and sense organs
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2008.10.007

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 D2 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 A2A (A2AR) but not A1 receptor (A1R) 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 A2AR density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A2AR. In these cells, A2AR agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A2AR. A significant correlation (r2 = 0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A2AR protein density. In conclusion, the A2AR is increased across different iron-insufficient conditions. The relation between A2AR and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.