Professor David J. BeechProfessor and Director of the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds
Free cytosolic Ca2+ and membrane potential are major determinants of cell function. Both are regulated by Ca2+-permeable non-selective cation channels. Protein superfamilies underlie these channels and one of them is the Transient Receptor Potential proteins (TRPs) which are encoded by 28 genes in mammals. TRPs form channels by assembling as tetramers which may be of mixed composition (heteromers).
One subfamily is the Canonical TRPs (TRPCs). All 7 TRPCs exist in humans except TRPC2. TRPCs are broadly expressed. An important heteromerising cluster is TRPC1, TRPC4 and TRPC5 (TRPC1/4/5). TRPC4 and TRPC5 form homomeric channels where as TRPC1 forms homomeric channels poorly, yet it readily forms heteromers with TRPC4 and TRPC5 – generating ion channels with distinct characteristics. TRPC1/4/5 channels have been implicated in complex biology including seizures, fear-related behaviour, heart failure and cancer. A major limitation on the field has been the absence of small-molecule modulators for probing the channels and exploring their possible therapeutic value.
Over the past 5 years Professor Beech’s team have led the way in a leap forward. A critical first step was their discovery of TRPC1/4/5 as the unexpected target of the African plant substance (-)-Englerin A. Surprisingly (-)-Englerin A causes potent and selective cancer cell death by triggering sustained sodium ion entry. We have now introduced a set of pharmacological tools for TRPC1/4/5 which include not only (-)-Englerin A but also Tonantzitlolone (high potency selective agonists) and Pico145 (a picomolar selective antagonist with graded subtype selectivity).
The talk will explain the background to this work, the discovery and properties of the small-molecules, and the exciting and unexpected biology which these molecules have so far enabled us to reveal.
About the speaker
Professor Beech graduated in Pharmacology from the University of Manchester UK in 1985 before PhD study with Thomas Bolton at St George’s Hospital Medical School London and postdoctoral training with Bertil Hille at the University of Washington Seattle USA.
In 1992 he established an independent research group at the University of Leeds UK, funded initially by a Wellcome Trust Postdoctoral Career Development Fellowship and then a full professorship since 2000. His research focusses on calcium-selective and calcium-permeable non-selective cationic channels of mammalian cells – their mechanisms, roles and potential as new therapeutic targets. He is particularly interested in the idea that the channels sense physical and chemical factors to regulate cardiovascular and metabolic health.
He has trained 74 postgraduate and postdoctoral research scientists, published 159 peer-reviewed articles (2 in Nature, 5 in Nature sister journals, H-index 54), filed 2 patents, and delivered 162 invited lectures worldwide.
He was elected to the Fellowship of the Academy of Medical Sciences in 2013 and became a Wellcome Trust Investigator in 2016 and British Heart Foundation Programme Grant Holder in 2018. Since 2016 he has been Director of the Leeds Institute of Cardiovascular and Metabolic Medicine, a research and student education organisation of over 200 staff in the School of Medicine at Leeds.
Professor Beech also founded and continues to direct the British Heart Foundation 4-Year PhD Programme in Cardiovascular Disease and Diabetes and the Multidisciplinary Cardiovascular Research Centre, a pan-university / teaching-hospital structure for all cardiovascular research in the Leeds region. For more information visit www.cardiovascular.leeds.ac.uk.
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