title: Pannexin 1 channels play essential roles in urothelial mechanotransduction and intercellular signaling.
abstract: Urothelial cells respond to bladder distension with ATP release, and ATP signaling within the bladder and from the bladder to the CNS is essential for proper bladder function. In other cell types, pannexin 1 (Panx1) channels provide a pathway for mechanically-induced ATP efflux and for ATP-induced ATP release through interaction with P2X7 receptors (P2X7Rs). We report that Panx1 and P2X7R are functionally expressed in the bladder mucosa and in immortalized human urothelial cells (TRT-HU1), and participate in urothelial ATP release and signaling. ATP release from isolated rat bladders induced by distention was reduced by the Panx1 channel blocker mefloquine (MFQ) and was blunted in mice lacking Panx1 or P2X7R expression. Hypoosmotic shock induced YoPro dye uptake was inhibited by MFQ and the P2X7R blocker A438079 in TRT-HU1 cells, and was also blunted in primary urothelial cells derived from mice lacking Panx1 or P2X7R expression. Rinsing-induced mechanical stimulation of TRT-HU1 cells triggered ATP release, which was reduced by MFQ and potentiated in low divalent cation solution (LDPBS), a condition known to enhance P2X7R activation. ATP signaling evaluated as intercellular Ca2+ wave radius was significantly larger in LDPBS, reduced by MFQ and by apyrase (ATP scavenger). These findings indicate that Panx1 participates in urothelial mechanotransduction and signaling by providing a direct pathway for mechanically-induced ATP release and by functionally interacting with P2X7Rs.
authors.affiliation: Department of Urology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Negoro
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Marcia
authors.initials: M
authors.lastname: Urban-Maldonado
authors.affiliation: Department of Urology, Cambridge Health Alliance, Cambridge, Massachusetts, United States of America.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Liou
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Spray
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Mia M
authors.initials: MM
authors.lastname: Thi
authors.affiliation: Department of Urology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Sylvia O
authors.initials: SO
authors.lastname: Suadicani
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D015767:Mefloquine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D000090324:Tumor Protein, Translationally-Controlled 1; D019459:Urothelium / Q000166:cytology / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D017630:Connexins; D009419:Nerve Tissue Proteins; C546468:P2RX7 protein, human; C492764:PANX1 protein, human; C503631:Panx1 protein, mouse; D058486:Receptors, Purinergic P2X7; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; C479936:pannexin 1, rat; D000255:Adenosine Triphosphate; D002118:Calcium; D015767:Mefloquine