The circadian regulation of extracellular ATP

Abstract

Extracellular ATP is a potent signaling molecule released from various cells throughout the body and is intimately involved in the pathophysiological functions of the nervous system and immune system by activating P2 purinergic receptors. Recent increasingly studies showed that extracellular ATP exhibits circadian oscillation with an approximately 24-h periodicity, which participates in regulatory pathways of central oscillator suprachiasmatic nucleus and peripheral oscillator bladder, respectively. Oscillators modulate the protein expression of ATP release channels and ectonucleotidase activity through clock genes; indeed, real-time alterations of ATP release and degradation determine outcomes of temporal character on extracellular ATP rhythm. The regulatory pathways on extracellular ATP rhythm are different in central and peripheral systems. In this review, we summarize the circadian rhythm of extracellular ATP and discuss several circadian regulatory pathways in different organs via ATP release and degradation, to provide a new understanding for purinergic signaling in the regulatory mechanism of circadian rhythm and a potential target to research the circadian regulation of extracellular ATP in other circadian oscillators.

Keywords: Bladder; Circadian rhythm; Extracellular ATP; Purinergic signalling; Suprachiasmatic nucleus.

Fig. 1

The regulation on pathway of eATP rhythm in central (prosencephalon, cortex, and SCN) and peripheral (serum and urothelium) systems. Molecular clocks in central and peripheral systems drive eATP rhythm by specific release pathways and degradation pathways. Regulation that impacts any rhythmic eATP release (e.g., Ca²⁺ channels, icon channel, exocytosis, or connexins) represents latent targets for controlling circadian pathways by molecular clocks (Bmal1, Clock, and Per) at organs and tissues. Shown are on the top the degradation pathway regulated by melatonin in the prosencephalon through CD39 and mediated by restraint stress in serum via ATPase. Upper right clock of icon denotes its own circadian rhythm. + indicates release pathway;—indicates degradation pathway