Detrusor overactivity is associated with downregulation of large-conductance calcium- and voltage-activated potassium channel protein

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.

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

“…Interestingly, BKα knockout mice (20) display a functionally incontinent phenotype, presumably due to detrusor overactivity. Furthermore, a number of studies (21,22) have suggested that the expression of BK channels is reduced in patients suffering from neurogenic detrusor overactivity. These results suggest that BK channel activators could represent a novel therapeutic approach for treating overactive bladder.…”

Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels

“…Antimuscarinic drugs, which are currently the primary pharmacologic therapy for OAB, have adverse side effects and limited effectiveness (1). Since BK channels have been identified to play a prominent role in the regulation of DSM excitability and contractility, they may be a valid pharmacological target for the treatment of bladder disorders such as OAB (5,15,20,23,31,34,35,38). Development of drugs that can enhance BK channel activity have been proposed and investigated particularly as a treatment option for urinary bladder dysfunction (3,4,17,37).…”

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca2+ Sensitization of Smooth Muscle Contraction

“…Bladder outlet obstruction is considered one of the key factors in BPH-induced lower urinary tract symptoms (LUTS) in aged men (41,42), and it is associated with remodeling and hypertrophy of the BSM that eventually leads to contractile dysfunction (41,42). PBOO-induced smooth muscle remodeling and hypertrophy are associated with altered expression of contractile, signaling, and regulatory proteins (16,20,29,35,(43)(44)(45)(46). Similar to the murine PBOO model, we observed increased expression of NF-B c-Rel and p50 in BSM from obstructed bladders compared with their expression in bladders from healthy controls (Fig.…”