Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder

F. Sprossmann, P. Pankert, U. Sausbier, A. Wirth, X. B. Zhou, J. Madlung, H. Zhao, I. Bucurenciu, A. Jakob, T. Lamkemeyer, W. Neuhuber, S. Offermanns, M. J. Shipston, M. Korth, A. Nordheim, P. Ruth, M. Sausbier

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The large-conductance, voltage-dependent and Ca2+-dependent K+ (BK) channel links membrane depolarization and local increases in cytosolic free Ca2+ to hyperpolarizing K+ outward currents, thereby controlling smooth muscle contractility. Constitutive deletion of the BK channel in mice (BK-/-) leads to an overactive bladder associated with increased intravesical pressure and frequent micturition, which has been revealed to be a result of detrusor muscle hyperexcitability. Interestingly, time-dependent and smooth muscle-specific deletion of the BK channel (SM-BK)(-/-)) caused a more severe phenotype than displayed by constitutive BK-/- mice, suggesting that compensatory pathways are active in the latter. In detrusor muscle of BK-/- but not SM- BK-/- mice, we found reduced L-type Ca2+ current density and increased expression of cAMP kinase (protein kinase A; PKA), as compared with control mice. Increased expression of PKA in BK-/- mice was accompanied by enhanced beta-adrenoceptor/cAMP-mediated suppression of contractions by isoproterenol. This effect was attenuated by about 60-70% in SM- BK-/- mice. However, the Rp isomer of adenosine-3',5'-cyclic monophosphorothioate, a blocker of PKA, only partially inhibited enhanced cAMP signaling in BK-/- detrusor muscle, suggesting the existence of additional compensatory pathways. To this end, proteome analysis of BK-/- urinary bladder tissue was performed, and revealed additional compensatory regulated proteins. Thus, constitutive and inducible deletion of BK channel activity unmasks compensatory mechanisms that are relevant for urinary bladder relaxation.
Original languageEnglish
Pages (from-to)1680-1697
Number of pages18
JournalThe FEBS Journal
Volume276
Issue number6
DOIs
Publication statusPublished - Mar 2009

Keywords / Materials (for Non-textual outputs)

  • cAMP/PKA signaling
  • overactive urinary bladder
  • proteomic adaptation
  • smooth muscle-specific BK channel knockout mice
  • time-dependent BK channel deletion

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