Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel.
Small conductance, calcium-activated potassium (SK) channels have an important role in determining the excitability and contractility of urinary bladder smooth muscle. Here, the role of the SK isoform SK3 was examined by altering expression levels of the SK3 gene using a mouse model that conditionally overexpresses SK3 channels (SK3T/T). Prominent SK3 immunostaining was found in both the smooth muscle (detrusor) and urothelium layers of the urinary bladder. SK currents were elevated 2.4-fold in isolated myocytes from SK3T/T mice. Selective suppression of SK3 expression by dietary doxycycline (DOX) decreased SK current density in isolated myocytes, increased phasic contractions of isolated urinary bladder smooth muscle strips and exposed high affinity effects of the blocker apamin of the SK isoforms (SK1-3), suggesting an additional participation from SK2 channels. The role of SK3 channels in urinary bladder function was assessed using cystometry in conscious, freely moving mice. The urinary bladders of SK3T/T had significantly greater bladder capacity, and urine output exceeded the infused saline volume. Suppression of SK3 channel expression did not alter filling pressure, threshold pressure or bladder capacity, but micturition pressure was elevated compared to control mice. However, SK3 suppression did eliminate excess urine production and caused a marked increase in non-voiding contractions. The ability to examine bladder function in mice in which SK3 channel expression is selectively altered reveals that these channels have a significant role in the control of non-voiding contractions in vivo. Activation of these channels may be a therapeutic approach for management of non-voiding contractions, a condition which characterizes many types of urinary bladder dysfunctions including urinary incontinence.
Herrera
Gerald M
GM
Department of Pharmacology, University of Vermont, Burlington 05405-0068, USA.
Pozo
Maria J
MJ
Zvara
Peter
P
Petkov
Georgi V
GV
Bond
Chris T
CT
Adelman
John P
JP
Nelson
Mark T
MT
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009122:Muscle Hypertonia / Q000503:physiopathology; D009130:Muscle, Smooth / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics* / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001743:Urinary Bladder / Q000502:physiology*; D001745:Urinary Bladder Diseases / Q000503:physiopathology*; D014556:Urine
C496900:Kcnn3 protein, mouse; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin