The Na+/Ca2+ exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca2+ dynamics.
The relative importance of the two Ca2+ transport modes of NCX activity leading to Ca2+ efflux (forward) and influx (reverse) in smooth muscle, however, remain unclear. Unexpectedly, spontaneous contractions of urinary bladder smooth muscle (UBSM) were enhanced in transgenic mice overexpressing NCX1.3 (NCX1.3tg/tg). The enhanced activity was attenuated by KB-R7943 or SN-6. Whole-cell outward NCX current sensitive to KB-R7943 or Ni2+ was readily detected in UBSM cells from NCX1.3tg/tg, but not in wild-type mice. Spontaneous Ca2+ transients in myocytes of NCX1.3tg/tg were larger and frequently resulted in propagating events and global elevations in cytosolic Ca2+ concentration. Significantly, NCX1.3tg/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-)NCX1.3tg/tg mice. We conclude that NCX1.3 overexpression is associated with abnormal urination owing to enhanced Ca2+ influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca2+ 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.
Written by:
Yamamura H, Cole WC, Kita S, Hotta S, Murata H, Suzuki Y, Ohya S, Iwamoto T, Imaizumi Y. Are you the author?
Nagoya City University Graduate School of Pharmaceutical Sciences.
Reference: Am J Physiol Cell Physiol. 2013 May 22. Epub ahead of print.
doi: 10.1152/ajpcell.00065
PubMed Abstract
PMID: 23703524
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