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Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder
Author(s) -
Sprossmann Franz,
Pankert Patrick,
Sausbier Ulrike,
Wirth Angela,
Zhou XiaoBo,
Madlung Johannes,
Zhao Hong,
Bucurenciu Iancu,
Jakob Andreas,
Lamkemeyer Tobias,
Neuhuber Winfried,
Offermanns Stefan,
Shipston Michael J.,
Korth Michael,
Nordheim Alfred,
Ruth Peter,
Sausbier Matthias
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.06900.x
Subject(s) - knockout mouse , overactive bladder , mutagenesis , bk channel , microbiology and biotechnology , chemistry , neuroscience , biology , endocrinology , medicine , genetics , mutation , receptor , gene , pathology , potassium channel , alternative medicine
The large‐conductance, voltage‐dependent and Ca 2+ ‐dependent K + (BK) channel links membrane depolarization and local increases in cytosolic free Ca 2+ 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 Ca 2+ 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.