BK channels as Pharmacological targets for therapeutic intervention

The BK channel is a large calcium and voltage gated potassium channel consisting of two different sub-units, α and β’s, these associate in cell membranes to control flow of potassium ions, which amongst other things, controls vascular tone (and blood pressure). Epidemiological evidence shows that women are less likely to suffer from high blood pressure than men and this has been attributed to the protective influence of oestrogens. We have been investigating the effects of oestrogen and membrane impermeant oestrogen derivatives on the Maxi K channel with the hope of developing a novel therapy for hypertension.

Project timeframes

The project ran began in 2010 and is ongoing.

Project aims

The aim of this project is to discover novel modulators of BK function with therapeutic potential. We also aim to gain a better understanding of the mechanism by which xeno-oestrogens regulate BK channels.

Project findings and impact

We have synthesised novel organ specific modulators for the BK channel. These modulators have been shown to be arterial vasodilators and their effects are due to the activation of vascular BK channels. In addition, these novel lead compounds may have use in the treatment of urinary incontinence and erectile dysfunction, as BK channels are known to be important in the pathophysiology of these age related conditions.

Research team

Dr Marcus Allen

Dr Jackie Maher

Dr Jon Mabley

Output

J Maher, A C Hunter, J G Mabley, J Lippiat and M C Allen. Smooth muscle relaxation and activation of the large conductance Ca++ –activated K+ (BKCa) channel by novel oestrogens. British Journal of Pharmacology (2013) 169 1153–1165 1153

De Wet H., Lippiat, J. D., Allen, M. (2009) Analysing Steroid Modulation of BK(Ca) Channels Reconstituted into Planar Lipid Bilayers. Methods in molecular biology 1064-3745

De Wet H, Allen MC, Holmes C, Stobbart M, Lippiat JD, Callaghan R (2006) Modulation of the BK Channel by estrogens: examination at a single channel level. Molecular Membrane Biology 23, 420-429 (peer reviewed journal)

Partners

This work is in collaboration with Dr Christy Hunter of Manchester University,  Dr H. de Wet, the Department of Physiology, University of Oxford, and Dr J. Lippiat, University of Leeds. And Dr Alice Rothnie of Aston University.