Detrusor overactivity is associated with downregulation of large-conductance calcium- and voltage-activated potassium
Shaohua Chang1, Cristiano Mendes Gomes, Joseph A Hypolite
1Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract:
Large-conductance voltage- and calcium-activated potassium (BK) channels have been shown to play a role in detrusor overactivity (DO). The goal of this study was to determine whether bladder outlet obstruction-induced DO is associated with downregulation of BK channels and whether BK channels affect myosin light chain 20 (MLC(20)) phosphorylation in detrusor smooth muscle (DSM). Partial bladder outlet obstruction (PBOO) was surgically induced in male New Zealand White rabbits. The rabbit PBOO model shows decreased voided volumes and increased voiding frequency. DSM from PBOO rabbits also show enhanced spontaneous contractions compared with control. Both BK channel alpha- and beta-subunits were significantly decreased in DSM from PBOO rabbits. Immunostaining shows BKbeta mainly expressed in DSM, and its expression is much less in PBOO DSM compared with control DSM. Furthermore, a translational study was performed to see whether the finding discovered in the animal model can be translated to human patients. The urodynamic study demonstrates several overactive DSM contractions during the urine-filling stage in benign prostatic hyperplasia (BPH) patients with DO, while DSM is very quiet in BPH patients without DO. DSM biopsies revealed significantly less BK channel expression at both mRNA and protein levels. The degree of downregulation of the BK beta-subunit was greater than that of the BK alpha-subunit, and the downregulation of BK was only associated with DO, not BPH. Finally, the small interference (si) RNA-mediated downregulation of the BK beta-subunit was employed to study the effect of BK depletion on MLC(20) phosphorylation. siRNA-mediated BK channel reduction was associated with an increased MLC(20) phosphorylation level in cultured DSM cells. In summary, PBOO-induced DO is associated with downregulation of BK channel expression in the rabbit model, and this finding can be translated to human BPH patients with DO. Furthermore, downregulation of the BK channel may contribute to DO by increasing the basal level of MLC(20) phosphorylation.
Insights
Large-conductance potassium (BK) channels are downregulated in detrusor overactivity (DO) models and patients. This BK channel reduction in smooth muscle may increase phosphorylation, contributing to DO.
Area of Science:
- Urology
- Physiology
- Molecular Biology
Background:
- Large-conductance voltage- and calcium-activated potassium (BK) channels are implicated in detrusor overactivity (DO).
- The role of BK channel expression and its impact on detrusor smooth muscle (DSM) phosphorylation in DO remains unclear.
Purpose of the Study:
- To investigate the association between bladder outlet obstruction-induced DO and BK channel downregulation in DSM.
- To determine if BK channel expression affects myosin light chain 20 (MLC(20)) phosphorylation in DSM.
- To translate findings from an animal model to human patients with benign prostatic hyperplasia (BPH) and DO.
Main Methods:
- Surgical induction of partial bladder outlet obstruction (PBOO) in rabbits.
- Assessment of voiding parameters, spontaneous DSM contractions, and BK channel subunit expression (alpha and beta) via immunostaining.
- Urodynamic studies and DSM biopsy analysis in human BPH patients with and without DO.
- Small interfering (si) RNA-mediated downregulation of BK beta-subunit in cultured DSM cells to assess MLC(20) phosphorylation.
Main Results:
- PBOO in rabbits led to decreased voided volumes, increased voiding frequency, enhanced DSM contractions, and significant downregulation of both BK alpha- and beta-subunits.
- Human BPH patients with DO exhibited overactive DSM contractions and significantly reduced BK channel expression (mRNA and protein) compared to those without DO.
- BK beta-subunit downregulation was more pronounced than alpha-subunit, correlating specifically with DO, not BPH itself.
- siRNA-mediated BK channel reduction in cultured DSM cells resulted in increased MLC(20) phosphorylation.
Conclusions:
- Partial bladder outlet obstruction-induced DO is associated with BK channel downregulation in rabbit DSM.
- This downregulation of BK channels is observed in human BPH patients with DO and is linked to increased MLC(20) phosphorylation.
- BK channel downregulation may be a contributing factor to the pathophysiology of DO by elevating basal MLC(20) phosphorylation in DSM.
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