Regulation of cardiac ion channels by carbon monoxide

Carbon monoxide (CO) poisoning accounts for more than 50% of all fatal poisonings, and the organs most susceptible to damage are the heart and brain. While chronic CO exposure can induce myocardial injury and fibrosis, acute exposure is associated with a disruption of ventricular repolarization and prolongation of the QT interval (termed long-QT (LQT) syndrome), thereby predisposing affected individuals to arrhythmias and even sudden death.

We have shown that several cardiovascular ion channels are important targets for modulation by CO and their regulation can contribute to the pro-arrhythmic effects of this gas. For example, pro-arrhythmic / LQT-like effects of CO may be due, at least in part, to its ability to modulate the activity of Nav1.5 and hERG-1 (see further reading, below, and unpublished observations); inheritable mutations in these channels are known to cause LQT3 and LQT2 respectively. KCNQ1 encodes the a-subunit of the voltage-gated potassium channel KvLQT1 (also known as Kv7.1) that co-assembles with KCNE1 (a-subunit, also known as minK) in vivo to form channels that gives rise to IKs, the slow delayed rectifier K+ current which plays an important role in repolarization during phase 3 of the cardiac action potential. The importance of KvLQT1 is reflected in the fact that numerous inheritable mutations in KCNQ1 give rise to LQT1, the most common of the LQT syndromes.

In this multidisciplinary study we shall explore the modulation of IKs and other ion channels contributing to the cardiac action potential using a range of complementary cell biology techniques including patch-clamp electrophysiology, molecular biology and confocal laser-scanning microscopy. We will fully characterise the molecular mechanisms and structural requirements underlying CO-mediated regulation of these channels, and determine the significance of such modulation to arrhythmia generation. Our studies will therefore further develop our understanding of (and hence treatment of) CO-induced arrhythmias. The project will be co-supervised by Dr John Boyle and Professor Derek Steele.