Effects of the novel BK (KCa 1.1) channel opener GoSlo-SR-5-130 are dependent on the presence of BKβ subunits.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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: R J Large, A Kshatri, T I Webb, S Roy, A Akande, E Bradley, G P Sergeant, K D Thornbury, N G McHale, M A Hollywood
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 10 Pg. 2544-56 (May 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25598230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• Anthraquinones
• GoSlo-SR-5-130
• GoSlo-SR-5-6
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits
• Protein Subunits
• Sulfonic Acids

Topics

• Animals
• Anthraquinones (pharmacology)
• Cells, Cultured
• HEK293 Cells
• Humans
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits (agonists, physiology)
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits (agonists, physiology)
• Membrane Potentials (drug effects, physiology)
• Muscle Contraction (drug effects, physiology)
• Muscle, Smooth (drug effects, physiology)
• Protein Subunits (agonists, genetics, physiology)
• Rabbits
• Sulfonic Acids (pharmacology)
• Transfection
• Urinary Bladder (drug effects, physiology)