Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel
Andrea L Meredith1, Kevin S Thorneloe, Matthias E Werner
1Department of Molecular and Cellular Physiology and the Howard Hughes Medical Institute, 279 Campus Drive, Stanford University, Stanford, CA 94305, USA.
Abstract:
BK large conductance voltage- and calcium-activated potassium channels respond to elevations in intracellular calcium and membrane potential depolarization, braking excitability of smooth muscle. BK channels are thought to have a particularly prominent role in urinary bladder smooth muscle function and therefore are candidate targets for overactive bladder therapy. To address the role of the BK channel in urinary bladder function, the gene mSlo1 for the pore-forming subunit of the BK channel was deleted. Slo(-/-) mice were viable but exhibited moderate ataxia. Urinary bladder smooth muscle cells of Slo(-/-) mice lacked calcium- and voltage-activated BK currents, whereas local calcium transients ("calcium sparks") and voltage-dependent potassium currents were unaffected. In the absence of BK channels, urinary bladder spontaneous and nerve-evoked contractions were greatly enhanced. Consistent with increased urinary bladder contractility caused by the absence of BK currents, Slo(-/-) mice demonstrate a marked elevation in urination frequency. These results reveal a central role for BK channels in urinary bladder function and indicate that BK channel dysfunction leads to overactive bladder and urinary incontinence.
Insights
Large conductance voltage- and calcium-activated potassium (BK) channels are crucial for urinary bladder function. Their absence in mice led to enhanced bladder contractions and overactive bladder symptoms, indicating their therapeutic potential.
Area of Science:
- Physiology
- Pharmacology
- Urology
Background:
- Large conductance voltage- and calcium-activated potassium (BK) channels regulate smooth muscle excitability.
- BK channels are implicated in urinary bladder function and are potential therapeutic targets for overactive bladder.
- The specific role of BK channels in bladder smooth muscle requires further elucidation.
Purpose of the Study:
- To investigate the role of the BK channel in urinary bladder function.
- To determine the effects of BK channel deletion on bladder smooth muscle activity and voiding behavior.
Main Methods:
- Generation of mSlo1 gene-deleted (Slo(-/-)) mice lacking the pore-forming subunit of BK channels.
- Electrophysiological recordings to assess BK currents in urinary bladder smooth muscle cells.
- Measurement of spontaneous and nerve-evoked bladder contractions.
- Observation of urination frequency in wild-type and Slo(-/-) mice.
Main Results:
- Slo(-/-) mice exhibited normal viability but moderate ataxia.
- Urinary bladder smooth muscle cells from Slo(-/-) mice lacked BK currents, while other potassium currents and calcium transients remained unaffected.
- Absence of BK channels resulted in significantly enhanced spontaneous and nerve-evoked bladder contractions.
- Slo(-/-) mice displayed a marked increase in urination frequency, indicative of overactive bladder.
Conclusions:
- BK channels play a critical role in regulating urinary bladder smooth muscle function.
- Dysfunction or absence of BK channels leads to enhanced bladder contractility and overactive bladder symptoms, including urinary incontinence.
- Targeting BK channels represents a promising therapeutic strategy for treating overactive bladder.
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