Cryptochrome Mediates Circadian Regulation of cAMP Signaling

During fasting, mammals maintain glucose homeostasis by stimulating hepatic gluconeogenesis1. Elevations in circulating glucagon (GLU) and epinephrine trigger the cAMP mediated phosphorylation of Creb and dephosphorylation of the Creb coactivator Crtc22. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment3–6. Here we show that Creb activity during fasting is modulated by Cryptochromes (Cry1 and Cry2), core components of the clock that are rhythmically expressed in the liver. Cry was elevated during the night/day transition, when it reduced fasting gluconeogenic gene expression by blocking GLU-mediated increases in intracellular cAMP concentrations and in the PKA-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry inhibited accumulation of cAMP in response to G protein coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry appeared to modulate GPCR activity directly Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use