Fig. 7. Model of clock regulation of xenobiotic efflux at the BBB.

Core circadian clock transcription factors BMAL1 and CLOCK activate transcription of Trpm7. Increased TRPM7 allows for higher intracellular free magnesium, which regulate the activity of xenobiotic transporters. Higher transporter activity decreases the level of xenobiotics in the brain. In the absence of BMAL1/CLOCK, TRPM7 and therefore free intracellular magnesium is low. Lower levels of magnesium are associated with decrease the activity of the xenobiotic transporters, thus xenobiotics are retained in the brain.