Inactivation Of HERG Potassium Channels: Dynamic Changes In The Outer Pore Structure
Funder
National Health and Medical Research Council
Funding Amount
$422,716.00
Summary
Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic me ....Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic mechanisms underlying arrhythmias. The rhythm of the heart beat is controlled by electrical signals mediated by the flow of ions through specialised proteins called ion channels. Of the channels that contribute to cardiac electrical activity, potassium ion channels encoded by the Human ether-a-go-go-related gene (HERG) have been of particular interest for three reasons. Firstly, mutations in HERG are the cause of one third of cases of congenital long QT syndrome, an inherited cause of sudden cardiac death. Secondly, HERG is the molecular target for the vast majority of drugs that cause drug-induced long QT syndrome, the commonest cause of drug-induced arrhythmias and cardiac death. Thirdly, HERG channels have very unusual biophysical properties, which has led to the suggestion that they may act as an endogenous anti-arrhythmic agent . Accordingly, the major objective of the proposed research program is to understand the molecular and structural basis of the unusual properties of HERG channels. We will use a combination of molecular and electrical techiques in conjunction with computer modeling to probe the micoscopic motions in the channel that underly the unusual biophyscial properties of these channels. This work will facilitate a better understanding of how clinically identified mutations in HERG contribute to the increased risk of cardiac arrhythmias. More generally, it will improve our understanding of how cardiac ion channels maintain the normal rhythm of the heart.Read moreRead less
The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of ions. The movement of ions across heart cell membranes is predominantly mediated by ion channel proteins. One of these proteins, called HERG, has some very unusual properties that make it well suited for suppressing abnormal heart beats. We propose to undertake a detailed investigation of the mechanisms by which HERG channels open and close. The results will provided a greater understanding of how HER ....The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of ions. The movement of ions across heart cell membranes is predominantly mediated by ion channel proteins. One of these proteins, called HERG, has some very unusual properties that make it well suited for suppressing abnormal heart beats. We propose to undertake a detailed investigation of the mechanisms by which HERG channels open and close. The results will provided a greater understanding of how HERG channels work and how altered function of HERG channels in patients with heart disease leads to an increased risk of abnormal heart rhythms and sudden cardiac death.Read moreRead less
Investigation Of Biological Ion Channels: Theoretical Formulation, Computer Simulation And Experimental Verification
Funder
National Health and Medical Research Council
Funding Amount
$677,292.00
Summary
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making ....All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making use of a powerful supercomputer, we propose to follow the motion of ions as they move through the channel, study how a channel can select only the correct type of ions to traverse it and determine how many ions a single channel is capable of processing per second. The predictions made by our theory and computer simulations will be checked experimentally. If the predictions and experimental findings do not agree, we will modify the theory and make new predictions.Read moreRead less
Characterisation And Regulation Of Chloride Channels In Cardiac And Skeletal Sarcoplasmic Reticulum In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$381,856.00
Summary
An understanding of the operation of ion channels in cell membranes is fundamental to our knowledge of the function of muscles under normal conditions and in pathological states that modify cell function, e.g. myotonia and cardiac failure. Ion channels control the flow of currents and the transport of substances which ultimately determine whether cells live or die, and hence whether cell pathologies are expressed as muscle failure, as when hypoxia causes tissue damage to the heart, or as severe ....An understanding of the operation of ion channels in cell membranes is fundamental to our knowledge of the function of muscles under normal conditions and in pathological states that modify cell function, e.g. myotonia and cardiac failure. Ion channels control the flow of currents and the transport of substances which ultimately determine whether cells live or die, and hence whether cell pathologies are expressed as muscle failure, as when hypoxia causes tissue damage to the heart, or as severe arrythmia or cardiac arrest. The objective is to understand channel involvement in the mechanisms underlying the function of cardiac and skeletal muscle. We believe that by mimicking the factors that occur in pathological conditions we can understand how ion channels are altered and controlled, and find ways of reversing harmful alterations, thereby reversing cell damage and failure of vital muscle function.Drugs will be used to modify the 'gating' of the channels. By comparing the effects of different drugs, we hope to determine the important features of the mechanisms that control the gating of the channels, making them more or less sensitive to different influences, especially those that occur in pathological states. The study has great application to the study of other pathologies, e.g. cystic fibrosis, severe diarrhoea, paralysis and chronic fatigue. The pharmacological emphasis offers the fundamental science needed to design novel and specific drugs to combat the many serious pathologies related to ion channel effects. Aside from its importance to basic science and to immediate issues of health, the study offers considerable economic gains, both through improved public health and through development of pharmaceuticals.Read moreRead less