Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock

Abstract

The circadian clock allows organisms to coordinate biochemical and physiological processes over one day. Changes in lighting conditions as they occur naturally over seasons or manmade by jet lag or shift work, advance or delay clock phase to synchronize physiology to the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to depend on both membrane depolarization and intracellular second-messenger signaling. In both processes, voltage-gated calcium channels (VGCCs) mediate calcium influx resulting in the activation of intracellular signaling pathways that activate Period ( Per ) gene expression. However, the precise mechanism how these processes are gated in a concerted manner is unknown. Here we show that cycling-dependent kinase 5 (Cdk5) activity is modulated by light and gates phase shifts of the circadian clock. We found that knock-down of Cdk5 in the SCN of mice affects phase delays but not phase advances. This is associated with uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA) – calcium calmodulin dependent kinase (CaMK) – cAMP response element-binding protein (CREB) signaling pathway. Accordingly, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified an important light modulated kinase that affects rapid clock phase adaptation. This finding indicates how light responsiveness and clock phase are coordinated to adapt activity onset to seasonal changes, jet-lag and shift work.