Inducible knockout mutagenesis reveals compensatorymechanisms elicited by constitutive BK channeldeficiency in overactive murine bladder
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...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
25 February 2009
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| In: |
The FEBS journal
Year: 2009, Volume: 276, Issue: 6, Pages: 1680-1697 |
| ISSN: | 1742-4658 |
| DOI: | 10.1111/j.1742-4658.2009.06900.x |
| Online Access: | Verlag, Volltext: https://doi.org/10.1111/j.1742-4658.2009.06900.x Verlag, Volltext: https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1742-4658.2009.06900.x 
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| Author Notes: | Franz Sprossmann, Patrick Pankert, Ulrike Sausbier, Angela Wirth, Xiao-Bo Zhou, Johannes Madlung, Hong Zhao, Iancu Bucurenciu, Andreas Jakob, Tobias Lamkemeyer, Winfried Neuhuber, Stefan Offermanns, Michael J. Shipston, Michael Korth, Alfred Nordheim, Peter Ruth and Matthias Sausbier |
| Summary: | 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 β-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. |
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| Item Description: | Gesehen am 11.11.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1742-4658 |
| DOI: | 10.1111/j.1742-4658.2009.06900.x |