title: Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3.
abstract: Pirt is a transmembrane protein predominantly expressed in peripheral neurons. However, the physiological and pathological roles of Pirt in hollow viscus are largely unknown. Here we show that Pirt deficiency in mice causes bladder overactivity. The density of α,β-meATP-induced currents is significantly reinforced in Pirt-deficient dorsal root ganglion (DRG) neurons. Pirt and P2X3 receptor co-localize in bladder nerve fibres and heterologous Pirt expression significantly reduces P2X3-mediated currents. Pirt interacts with P2X3 through the N-terminal 14 amino-acid residues. TAT-conjugated Pirt(N14) peptide (Pirt(N14)) is sufficient to inhibit P2X3 activation in bladder DRG neurons and to alleviate bladder overactivity in Pirt(-/-) mice. Pirt expression is decreased in the bladder of cyclophosphamide (CYP)-treated mice, a commonly used model of bladder overactivity. Importantly, Pirt(N14) administration reduces the frequency of bladder voiding and restores the voided volume of CYP-treated mice. Therefore, our results demonstrate that Pirt is an endogenous regulator of P2X3 in bladder function.
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Gao
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Feng
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zheng-Hua
authors.initials: ZH
authors.lastname: Xiang
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiu-Jie
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210046, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210046, China.
authors.forename: Zong-Xiang
authors.initials: ZX
authors.lastname: Tang
authors.affiliation: 1] The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, 725N Wolfe Street, Baltimore, Maryland 21205, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Xin-Zhong
authors.initials: XZ
authors.lastname: Dong
authors.affiliation: Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai 200433, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology; D018076:DNA, Complementary; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D058920:Purinergic P2X Receptor Antagonists; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D001743:Urinary Bladder / Q000294:innervation; D053201:Urinary Bladder, Overactive / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C529003:Pirt protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D058477:Receptors, Purinergic P2X3; D003520:Cyclophosphamide