Adenosine and other purinergic products in circadian timing

The circadian oscillator plays an important role in behavior and metabolic physiology. In turn, adenosine occupies a unique position as both a fundamental neuromodulator and a basic building block of cellular metabolism. Multiple connections exist between the two, both through the direct actions of adenosine and through the cellular signaling cascades regulating and regulated by its availability. Specifically, we show that the circadian clock is connected to adenosine and other purinergic products on three levels. At the level of circadian signaling, the adenosine-derived signaling molecule cAMP is itself a circadian clock component that indirectly induces transcription of many circadian genes, as well as influencing cell cycle timing. At the level of metabolism, AMP kinase, a cellular energy sensor dependent upon AMP, can phosphorylate multiple clock proteins. It phosphorylates cryptochromes and thereby enhances the activity of the inhibitory clock protein complex that contains them. The histone and clock protein deacetylase SIRT1 is also phosphorylated and upregulated by AMPK, leading to increased clock protein degradation and chromatin repression. SIRT1 activity is also regulated by NAD+ cofactors, whose levels are themselves under both circadian and metabolic control. Finally, multiple adenosine receptor subtypes can control clock function. A3 receptors influence mammalian temperature control and therefore possibly the circadian oscillator. A1 receptor transcription can be induced indirectly via glucocorticoids which are under circadian control. In addition, A1 receptors modulate light responsiveness of the circadian clock. Taken together, this intricate regulatory web likely permits a complex dialogue between metabolism and diurnal behavior and physiology that allows organisms to exploit their circadian geophysical environment optimally.