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| ID:
474464.0,
MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts |
| Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder |
| Authors: | Sprossmann, F.; Pankert, P.; Sausbier, U.; Wirth, A.; Zhou, X. B.; Madlung, J.; Zhao, H.; Bucurenciu, I.; Jakob, A.; Lamkemeyer, T.; Neuhuber, W.; Offermanns, S.; Shipston, M. J.; Korth, M.; Nordheim, A.; Ruth, P.; Sausbier, M. | | Date of Publication (YYYY-MM-DD): | 2009 | | Title of Journal: | FEBS J | | Volume: | 276 | | Issue / Number: | 6 | | Start Page: | 1680 | | End Page: | 97 | | Audience: | Not Specified | | Abstract / Description: | 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 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. | | Free Keywords: | Animals; Blotting, Western; Chromatography, High Pressure Liquid; Cyclic AMP/metabolism; Immunohistochemistry; Large-Conductance Calcium-Activated Potassium Channels/*genetics; Male; Mice; Mice, Knockout; Muscle Contraction; Mutagenesis; Proteomics; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Urinary Bladder/metabolism/physiopathology; Urinary Bladder, Overactive/*genetics | | External Publication Status: | published | | Document Type: | Article |
| Communicated by: | N. N. | | Affiliations: | MPI für physiologische und klinische Forschung | | External Affiliations: | Pharmakologie und Toxikologie, Institut fur Pharmazie, Universitat Tubingen, Germany.
| | Identifiers: | ISSN:1742-4658 (Electronic)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=.. | |
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