Received for publication March 4, 2008.
Revised June 15, 2008.
Accepted for publication June 20, 2008.

Caffeine stimulates cytochrome oxidase expression and activity in the striatum in a sexually-dimorphic manner

Abstract

Epidemiological studies indicate that caffeine consumption reduces the risk of Parkinson's disease (PD) in men, and antagonists of the adenosine 2A receptor ameliorate the motor symptoms of PD. These findings motivated us to identify proteins whose expression is regulated by caffeine in a sexually-dimorphic manner. Using mass spectroscopy, we found that Cox7c, a nuclear-encoded subunit of the mitochondrial enzyme cytochrome oxidase, is upregulated in the striatum of male but not female mice after receiving a single dose of caffeine. The expression of two other Cox subunits, Cox1 and Cox4, was also stimulated by caffeine in a male-specific fashion. This upregulation of Cox subunits by caffeine was accompanied by an increase in Cox enzyme activity in the male striatum. Caffeine-induced stimulation of Cox expression and activity were reproduced using the A2AR-specific antagonist SCH58261, and co-administration of the A2AR-specific agonist CGS21680 counteracted the elevation of Cox expression and activity by caffeine. Caffeine also increased Cox activity in PC12 cells. In contrast, siRNA knockdown of Cox7c expression in PC12 cells blunted Cox activity, and this was counteracted by caffeine treatment. Caffeine was also found to increase Cox7c mRNA expression in the striatum, and in PC12 cells. This occurred at the level of transcription and was mediated by a segment of the Cox7c promoter. Overall, these findings indicate that cytochrome oxidase is a metabolic target of caffeine, and that stimulation of Cox activity by caffeine via blockade of A2AR signaling may be an important mechanism underlying the therapeutic benefits of caffeine in PD.

Key words: Adenosine, Dopamine, Promoter analysis, Mass Spectroscopy, Regulation of gene expression, Enzymology, Regulation - transcriptional, RNA/siRNA, Caffeine, Excitotoxicity, neurodegeneration