Overexpression of small-conductance Ca2+-activated K+ channel 2 attenuates pain-like behavior in female mice with cystitis
Guadalupe Manrique-Maldonado, Xuejiao Sun, Allison L. Marciszyn, Nicolas Montalbetti, Marcelo D. Carattino
Guadalupe Manrique-Maldonado, Xuejiao Sun, Allison L. Marciszyn, Nicolas Montalbetti, Marcelo D. Carattino
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Research Article Nephrology Neuroscience

Overexpression of small-conductance Ca2+-activated K+ channel 2 attenuates pain-like behavior in female mice with cystitis

Abstract

Small-conductance Ca2+-activated K+ (SK) channels regulate neuronal excitability and act as a feedback mechanism to limit firing during sustained stimulation. In the present study, we demonstrated that SK2 plays an important role in the control of bladder function and visceral pain processing. SK2 channels are expressed in bladder-innervating afferent neurons, and ablation of this subunit results in elevated afferent firing rates in response to physiological levels of bladder distension, supporting a role for SK2 in modulating mechanosensory excitability. Mice overexpressing SK2 exhibit increased bladder capacity and reduced voiding frequency. Furthermore, overexpression of SK2 prevents the onset of pelvic mechanical allodynia and attenuates the exaggerated visceromotor response to bladder distension seen in wild-type mice with chemical cystitis. Thus, SK2 may be a promising target for treating overactive bladder and pain originating from the urinary bladder and other pelvic organs.

Authors

Guadalupe Manrique-Maldonado, Xuejiao Sun, Allison L. Marciszyn, Nicolas Montalbetti, Marcelo D. Carattino

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Figure 4

Overexpression of Kcnn2 in transgenic SK2 mice.

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Overexpression of Kcnn2 in transgenic SK2 mice. FISH and immuno-FISH con...
FISH and immuno-FISH confirm higher Kccn2 expression in tissues of SK2+/T mice than control littermates (WT). No signal was visible with the negative control probe (not shown). (A) Confocal images of the urinary bladder. FISH was performed with probes for Kcnn2 and Acta2. Acta2 is highly expressed in smooth muscle cells. Insets: 4-fold magnification of the muscularis externa. Note the overlap between Kcnn2 and Acta2. Mu, mucosa; ME, muscularis externa. Scale bars: 200 μm. (B) Quantification of Kcnn2 expression in the bladder muscularis externa. The fraction area of the muscularis externa occupied by Kcnn2 clusters is shown. Data are shown as the mean ± SEM (WT, n = 4; SK2+/T, n = 4; Mann-Whitney test, *P < 0.05). (C) Confocal images of DRG. Immuno-FISH was performed in fresh-frozen sections of DRG (L6–S2) harvested from mice injected into the bladder wall with cholera toxin β subunit (CTb). A goat anti-CTb antibody and a secondary donkey anti-goat antibody conjugated with Alexa Fluor 594 were used to identify bladder sensory neurons (red). Insets: 4-fold magnification of CTb-labeled neurons. Scale bars: 100 μm. (D) Quantification of Kcnn2 expression in CTb-labeled neurons. The fraction area of each CTb-labeled neuron occupied by Kcnn2 clusters is shown. Data are shown as the mean ± SEM (WT, 78 cells from 2 mice; SK2+/T, 133 cells from 2 mice; Mann-Whitney test, *P < 0.05).