Piezo: a cardiac stretch-activated ion channel?
Year of award: 2015
Grantholders
Dr Barry Denholm
University of Edinburgh
Project summary
The heart senses and adapts to its own highly dynamic mechanical environment. This environment changes beat-by-beat, and over longer timescales due to physiological changes or disease. Failure to detect and adjust performance accordingly is associated with arrhythmias and sudden cardiac death. The molecular and cellular basis for this adaptation is not known, but mechanosensitive ion channels are thought to be key components. Preliminary data from our lab using the Drosophila heart model identify the stretch-activated Ca2+-permeable ion channels of the Piezo family as being central to this adaptive response. We propose that as the myocardium undergoes mechanical stretch when blood fills the heart, Piezo channels open, elevating intracellular Ca2+ leading to heightened cardiomyocyte contraction; thus aligning mechanical status with cardiac performance. This predicts that Piezo-/- hearts will be refractory to mechanical stretch, will have abnormal Ca2+ signalling, and will exhibit defects in contractility.
We will compare the parameters between wild-type and Piezo-/- hearts. Our data indicate that Piezo is a sarcoplasmic reticulum-resident channel. We will extend this observation to determine the precise subcellular focus of Piezo activity and use the power of Drosophila molecular genetics to identify further components of the Piezo pathway.