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Effects of the novel BK (K Ca 1.1) channel opener GoSlo ‐ SR ‐5‐130 are dependent on the presence of BK β subunits
Author(s) -
Large R J,
Kshatri A,
Webb T I,
Roy S,
Akande A,
Bradley E,
Sergeant G P,
Thornbury K D,
McHale N G,
Hollywood M A
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13085
Subject(s) - bk channel , iberiotoxin , chemistry , contractility , hek 293 cells , protein subunit , biophysics , potassium channel , microbiology and biotechnology , biochemistry , endocrinology , biology , receptor , membrane potential , gene
Background and Purpose GoSlo ‐ SR compounds are efficacious BK (K Ca 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 BK α alone or in combination with either β 1 or β 4 subunits. Key Results GoSlo ‐ SR ‐5‐6 shifted the voltage required for half maximal activation ( V 1/2 ) 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 V 1/2 in smooth muscle cells by approximately −100 mV; however, this was reduced by ∼80% in HEK cells expressing only BK α subunits. When β 1 or β 4 subunits were co‐expressed with BK α, 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 β 1 or β 4 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.