title: Effects of the novel BK (KCa 1.1) channel opener GoSlo-SR-5-130 are dependent on the presence of BKβ subunits.
abstract: OBJECTIVE
  GoSlo-SR compounds are efficacious BK (KCa 1.1) channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions.
  
  
  METHODS
  A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BKα alone or in combination with either β1 or β4 subunits.
  
  
  RESULTS
  GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2 ) of BK channels approximately -100 mV, irrespective of the presence of regulatory β subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by approximately -100 mV; however, this was reduced by ∼80% in HEK cells expressing only BKα subunits. When β1 or β4 subunits were co-expressed with BKα, efficacy was restored. GoSlo-SR-5-130 caused a concentration-dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels.
  
  
  CONCLUSIONS
  GoSlo-SR-5-130 required β1 or β4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of β subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. The novel BK channel opener, GoSlo-SR-5-130, is approximately fivefold more efficacious on BK channels with regulatory β subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder.
authors.affiliation: The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co. Louth, Ireland.
authors.forename: R J
authors.initials: RJ
authors.lastname: Large
authors.forename: A
authors.initials: A
authors.lastname: Kshatri
authors.forename: T I
authors.initials: TI
authors.lastname: Webb
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: A
authors.initials: A
authors.lastname: Akande
authors.forename: E
authors.initials: E
authors.lastname: Bradley
authors.forename: G P
authors.initials: GP
authors.lastname: Sergeant
authors.forename: K D
authors.initials: KD
authors.lastname: Thornbury
authors.forename: N G
authors.initials: NG
authors.lastname: McHale
authors.forename: M A
authors.initials: MA
authors.lastname: Hollywood
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists / Q000502:physiology; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000819:agonists / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D013451:Sulfonic Acids / Q000494:pharmacology*; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D000880:Anthraquinones; C000607770:GoSlo-SR-5-130; C000607769:GoSlo-SR-5-6; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D021122:Protein Subunits; D013451:Sulfonic Acids