ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y(6) receptors

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Alexandrina Timoteo, MA (Author) Other; Carneiro, I (Author) Other; Silva, I (Author) Other; Noronha Matos, JB (Author) FMUP; Ferreirinha, F (Author) Other; Silva Ramos, M (Author) Other; Paulo Correia de Sá (Author) ICBAS

Journal

Title: Biochemical Pharmacology

Vol. 87

Pages: 371-379

ISSN: 0006-2952

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 41 Citations

Scopus - 44 Citations

Other information

Authenticus ID: P-008-Z06

DOI: 10.1016/j.bcp.2013.11.007

Abstract (EN): In contrast to the well-known signaling role of urothelial ATP to control bladder function, the hypothesis that uracil nucleotides (UTP and/or UDP) also exert autocrine/paracrine actions only recently gained experimental support. Urothelial cells express UDP-sensitive P2Y(6) receptors, yet their role in the control of bladder activity has been mostly neglected. This study was designed to investigate the ability of PSB0474, a stable UDP analogue which exhibits selectivity for P2Y(6) receptors, to modulate urodynamic responses in the anaesthetized rat in vivo. Instillation of PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (At) of bladder contractions. PSB0474-induced bladder overactivity was prevented by the selective P2Y(6) antagonist, MRS2578. The increase in the VF produced by PSB0474 was also blocked by inhibitors of pannexin-1 hemichannels, (10)Panx or carbenoxolone, when these drugs were applied inside the bladder lumen but not when they were administered intravenously. Reduction of hemichannels pore permeability with H1152 also prevented PSB0474-induced bladder overactivity, but the exocytosis inhibitor, Exo-1, was inactive. PSB0474 increased by 3-fold the urinary ATP content. Implication of hemichannels permeability on PSB0474-induced ATP release was demonstrated by real-time fluorescence video-microscopy measuring the uptake of propidium iodide by intact urothelial cells in the absence and in the presence of MRS2578 or carbenoxolone. Confocal microscopy studies confirmed the co-localization of pannexin-1 and P2Y(6) receptors in the rat urothelium. Data indicate that activation of P2Y(6) receptors causes bladder overactivity in the anaesthetized rat indirectly by releasing ATP from the urothelium via pannexin-1 hemichannels.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9