Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel.
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.
Meredith
Andrea L
AL
Department of Molecular and Cellular Physiology and the Howard Hughes Medical Institute, 279 Campus Drive, Stanford University, Stanford, CA 94305, USA.
Thorneloe
Kevin S
KS
Werner
Matthias E
ME
Nelson
Mark T
MT
Aldrich
Richard W
RW
D000483:Alleles; D000818:Animals; D001259:Ataxia; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D005838:Genotype; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D019076:Transgenes; D001743:Urinary Bladder / Q000378:metabolism; D014549:Urinary Incontinence / Q000235:genetics* / Q000473:pathology; D014554:Urination
D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011188:Potassium; D002118:Calcium