title: 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.
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.forename: Cristiano Mendes
authors.initials: CM
authors.lastname: Gomes
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hypolite
authors.forename: James
authors.initials: J
authors.lastname: Marx
authors.forename: Jaber
authors.initials: J
authors.lastname: Alanzi
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
authors.forename: Bruce
authors.initials: B
authors.lastname: Malkowicz
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists / Q000378:metabolism*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D014563:Urodynamics
chemical_list: D001562:Benzimidazoles; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D018994:Myosin Light Chains; D012333:RNA, Messenger; C086491:NS 1619; D011188:Potassium
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