title: Overactive bladder mediated by accelerated Ca2+ influx mode of Na+/Ca2+ exchanger in smooth muscle.
abstract: The Na(+)/Ca(2+) exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca(2+) dynamics. The relative importance of the two Ca(2+) transport modes of NCX activity leading to Ca(2+) efflux (forward) and influx (reverse) in smooth muscle, however, remains unclear. Unexpectedly, spontaneous contractions of urinary bladder smooth muscle (UBSM) were enhanced in transgenic mice overexpressing NCX1.3 (NCX1.3(tg/tg)). The enhanced activity was attenuated by KB-R7943 or SN-6. Whole cell outward NCX current sensitive to KB-R7943 or Ni(2+) was readily detected in UBSM cells from NCX1.3(tg/tg) but not wild-type mice. Spontaneous Ca(2+) transients in myocytes of NCX1.3(tg/tg) were larger and frequently resulted in propagating events and global elevations in cytosolic Ca(2+) concentration. Significantly, NCX1.3(tg/tg) mice exhibited a pattern of more frequent urination of smaller volumes and this phenotype was reversed by oral administration of KB-R7943. On the other hand, KB-R7943 did not improve it in KB-R7943-insensitive (G833C-)NCX1.3(tg/tg) mice. We conclude that NCX1.3 overexpression is associated with abnormal urination owing to enhanced Ca(2+) influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca(2+) release events and a potentiation of spontaneous UBSM contraction. These findings suggest the possibility that NCX is a candidate molecular target for overactive bladder therapy.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.forename: William C
authors.initials: WC
authors.lastname: Cole
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.forename: Shingo
authors.initials: S
authors.lastname: Hotta
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Murata
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001593:Benzyl Compounds / Q000494:pharmacology; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D001743:Urinary Bladder / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000378:metabolism*
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D000889:Anti-Arrhythmia Agents; D001593:Benzyl Compounds; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; D013890:Thiourea; D002118:Calcium
keywords: KB-R7943; overactive bladder; smooth muscle; sodium/calcium exchanger; urinary bladder