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Sci Rep. 2018 Jan 31;8(1):1996. doi: 10.1038/s41598-018-20379-0.

Circadian coordination of ATP release in the urothelium via connexin43 hemichannels.

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Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Department of Urology, Japanese Red Cross Otsu Hospital, Shiga, 520-8511, Japan.
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Department of Urology, Cambridge Health Alliance, Cambridge, MA, 02139, USA.
Department of Urology, Hyogo College of Medicine, Hyogo, 663-8501, Japan.
Department of Health Science, School of Pharmacy, Nihon University, Chiba, 245-8555, Japan.
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.


Day-night changes in the storage capacity of the urinary bladder are indispensable for sound sleep. Connexin 43 (Cx43), a major gap junction protein, forms hemichannels as a pathway of ATP in other cell types, and the urinary bladder utilizes ATP as a mechanotransduction signals to modulate its capacity. Here, we demonstrate that the circadian clock of the urothelium regulates diurnal ATP release through Cx43 hemichannels. Cx43 was expressed in human and mouse urothelium, and clock genes oscillated in the mouse urothelium accompanied by daily cycles in the expression of Cx43 and extracellular ATP release into the bladder lumen. Equivalent chronological changes in Cx43 and ATP were observed in immortalized human urothelial cells, but these diurnal changes were lost in both arrhythmic Bmal1-knockout mice and in BMAL1-knockdown urothelial cells. ATP release was increased by Cx43 overexpression and was decreased in Cx43 knockdown or in the presence of a selective Cx43 hemichannel blocker, which indicated that Cx43 hemichannels are considered part of the components regulating ATP release in the urothelium. Thus, a functional circadian rhythm exists in the urothelium, and coordinates Cx43 expression and function as hemichannels that provide a direct pathway of ATP release for mechanotransduction and signalling in the urothelium.

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