Normal cardiac electrical function relies on appropriate expression of ion channels in the myocardium and conducting tissues. Unregulated alterations in the pattern of channel expression can result in cardiac arrhythmias, which are one of the leading causes of mortality worldwide. How the correct patterns of ion channel expression are determined in different cells during cardiac development and what factors regulate final channel expression levels are poorly understood. A better understanding of these processes will provide insight into how the system can establish stable electrical function in the face of a wide variety of disturbances. One long term goal of this proposal is to understand the function of critical periods during the development of cardiac electrical function. These are periods when maturation of at least some aspects of electrical function appears to be subject to feedback regulation, possibly by sensing calcium fluxes into the cell. We have developed a mouse model of cardiac-specific inducible gene knockout of the ion channel subunit KChIP2 that allows us to study the nature and timing of one critical period. Our preliminary results show that KChIP2 gene knockout in adult animals produces a lethal deficit in cardiac electrical function. In marked contrast, if KChIP2 gene knockout is induced during the early postnatal period, the majority of mice survive, despite the importance of KChIP2 and the transient outward current for the electrical properties of mouse cardiac myocytes. The first goal of this application is to identify the mechanisms that lead to lethality following KCHIP2 gene knockout in the adult, using a combination of electrophysiological and molecular techniques. The second goal is to use the inducible knockout system to characterize the critical period in postnatal development during which the animals can effectively compensate for the loss of the KChIP2 subunit.
The electrical properties of the heart are determined by the pattern and level of ion channel genes expressed by different cardiac cell types. Alterations in this pattern often occur during the course of common cardiac pathologies, including heart failure and infarction. This process is known as electrical remodeling and is generally harmful in adults, leading to a significantly increased risk of arrhythmia. Electrical remodeling must have some useful purpose or it would not be retained during the course of evolution. We propose that feedback pathways controlling channel expression are of particular importance during development to help establish stable electrical function in the heart. The aim of this project is to understand the function of these remodeling mechanisms during the development of the heart's electrical system and to understand why these systems fail to perform appropriately in the adult, leading to arrhythmias.
|McKinnon, David; Rosati, Barbara (2016) Transmural gradients in ion channel and auxiliary subunit expression. Prog Biophys Mol Biol 122:165-186|