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Sci Rep. 2016 Jul 14;6:29761. doi: 10.1038/srep29761.

Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase.

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Department of Urology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Density, and Pharmaceutical Science, Okayama 700-8530, Japan.
Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan.
Department of Urology, Shiga University of Medical Science, Shiga 520-2192, Japan.
Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
Institute of Life Sciences, Ajinomoto Co. Inc., Kawasaki 210-8681, Japan.
Department of Endocrine and Metabolic Diseases/Diabetes Mellitus Kyushu University Hospital, Fukuoka 812-8582, Japan.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.


The bladder urothelium is more than just a barrier. When the bladder is distended, the urothelium functions as a sensor to initiate the voiding reflex, during which it releases ATP via multiple mechanisms. However, the mechanisms underlying this ATP release in response to the various stretch stimuli caused by bladder filling remain largely unknown. Therefore, the aim of this study was to elucidate these mechanisms. By comparing vesicular nucleotide transporter (VNUT)-deficient and wild-type male mice, we showed that ATP has a crucial role in urine storage through exocytosis via a VNUT-dependent mechanism. VNUT was abundantly expressed in the bladder urothelium, and when the urothelium was weakly stimulated (i.e. in the early filling stages), it released ATP by exocytosis. VNUT-deficient mice showed reduced bladder compliance from the early storage phase and displayed frequent urination in inappropriate places without a change in voiding function. We conclude that urothelial, VNUT-dependent ATP exocytosis is involved in urine storage mechanisms that promote the relaxation of the bladder during the early stages of filling.

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