Yamamura H, Cole WC, Kita S, Hotta S, Murata H, Suzuki Y, Ohya S, Iwamoto T, Imaizumi Y. Overactive bladder mediated by accelerated Ca 2ϩ influx mode of Na ϩ /Ca 2ϩ exchanger in smooth muscle. The Na ϩ / Ca 2ϩ exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca 2ϩ dynamics. The relative importance of the two Ca 2ϩ transport modes of NCX activity leading to Ca 2ϩ efflux (forward) and influx (reverse) in smooth muscle, however, remains unclear. Unexpectedly,

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... us 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 2ϩ was readily detected in UBSM cells from NCX1.3 tg/tg but not wild-type mice. Spontaneous Ca 2ϩ transients in myocytes of NCX1.3 tg/tg were larger and frequently resulted in propagating events and global elevations in cytosolic Ca 2ϩ 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 2ϩ influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca 2ϩ 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.