Caveolae are small omega shaped invaginations in the cell membrane. They are believed to be crucial in the regulation of cardiac activity in response to stress. The purpose of this project is to investigate the effects of caveolar currents on cardiac electrophysiology. In cardiac myocytes, caveolae are known to contain ion channels and their necks can be open or closed in response to adrenergic stimulation. In the open configuration, the caveolar necks create a low resistance pathway to the extracellular space thus presenting additional ion channels to the membrane. However, in the closed configuration, the caveolae and their ion channels are isolated from the plasma membrane and extracellular space. Caveolae are ubiquitous in cardiac myocytes (roughly 20,000-25,000 per cell) and application of a beta agonist has been shown trigger the opening of caveolar necks leading to an increase in sodium current of up to 40%. This caveolar current is incorporated into mathematical models of cardiac electrophysiology in order to address three fundamental questions. First, what is the role of caveolae in healthy heart? Answering this question requires simulations with a biophysically detailed model of the ventricular myocyte which includes the caveolar current. Changes in both single action potentials and periodically paced tissue are explored. Analysis (primarily dynamical systems, bifurcations and asymptotics) of a more tractable reduced model is also used to understand the results. Second, what is the behavior of caveolae in the closed configuration? The fundamental idea is that the channels inside a closed caveolae are exposed to a different voltage and different ionic concentration. These channels will therefore be in a different state than those on the exterior membrane and will behave differently when the caveolae opens. Because there are only a small number of channels per caveolae and because the caveolae are so small that the movement of a single ion across the membrane creates a significant change in voltage, a combination of continuum-deterministic and discrete-stochastic modeling is used. Third, how do mutations in the structural protein caveolin-3 lead to changes in the action potential and arrhythmias? The investigators hypothesize that caveolin-3 mutations can lead to changes in the opening and closing dynamics of the caveolar neck and that in some cases the neck can flicker open and close more quickly so that a single caveolae may change state one or more times within a single action potential. A probability density approach is used in which the density of states of the caveolae evolves.
Changes in the primary structural protein for caveolae, known as caveolin-3 can cause a host of caveolinopathies such as muscular dystrophy, hyperCKemia, myopathy, long QT syndrome (specifically LQTS9) and sudden infant death syndrome (LQTS3-like). Caveolae are therefore believed to play a key role in the regulation of cardiac electrical activity. However, their effect has not yet been incorporated into existing cardiac models. This project is among the first to model the regulatory effects of caveolae. Preliminary results show that including the dynamics of caveolae can have dramatic and unexpected effects on the cardiac action potential. This is a paradigm shift in caveolar research since the work up to this point has focused on the role of caveolae in signaling rather than their effects on electrophysiology. The long term goal of this research is to understand the role of caveolae as part of the healthy human adrenergic response and to investigate the various pathologies associated with caveolar mutations.
