Insight into 'switch' for stroke and heart disease
5 March 2012
Scientists investigating a ‘biochemical switch’ linked to strokes and heart disease claim to have made an advance in understanding how it is ‘turned on’. The breakthrough was announced today in the prestigious science journal Proceedings of the National Academy of Sciences. The work was led by a team at the University of Leicester, working in collaboration with Dr Mark Young Cardiff University (School of Biosciences), to investigate the ‘biochemical switch’ identified as the P2X1 receptor.
Lead researcher Professor Richard Evans, of the University of Leicester Department of Cell Physiology & Pharmacology, said: “P2X1 receptors are protein molecules expressed on blood platelets which are cells involved in blood clotting. Drugs that block these receptors have the potential to reduce “dangerous” blood clotting that leads to strokes and heart attacks.
“Our research has looked at how the P2X1 receptor is “turned on”. By biochemical studies and purifying the P2X1 receptor and using an electron microscope we have ‘visualised’ the receptor and detected changes in its shape when it is activated".
The work in this paper has given a much clearer picture of the receptor. It can be seen that the receptor has 3 identical parts (or subunits) which when 'activated' by ATP can change the receptor's shape by creating a twisting action between these parts.
Model of the human P2X1 receptor for ATP, the three subunits that make up the functional receptor are shown in red, white and blue.
If they then chemically 'locked' the receptor to stop this twisting, then the receptor could not be fully activated. This work will help to develop drugs that can stop the P2X1 receptor being “turned on” and these would be useful to prevent stroke and heart attack. These results will also enable structure-based drug design, leading to other new analgesic and anti-inflammatory therapies.
‘We have the first realistic insight into how a switch linked to blood-clotting, and therefore connected to strokes and heart-attacks, is operated’ – lead researcher Richard Evans.
The research was funded by the Wellcome Trust and the British Heart Foundation
For more information:
Dr M Young
Roberts JA, Allsopp RC, El Ajouz S, Vial C, Schmid R, Young MT and Evans RJ (2012) Agonist binding evokes extensive conformational changes in the extracellular domain of the ATP-gated human P2X1 receptor ion channel. Proc Natl Acad Sci USA Early edition 1201872109