Inducible Knockout Mutagenesis Reveals Compensatory Mechanisms Elicited by Constitutive BK Channel Deficiency in Overactive Murine Bladder

Overview

Journal FEBS J

Specialty Biochemistry

Date 2009 Feb 18

PMID 19220851

Citations 29

Authors

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

Matthias Sausbier

Affiliations

Soon will be listed here.

Abstract

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.

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