Excitation-contraction (EC) coupling is the coordinated process by which an action potential triggers cell contraction. It is initiated in specialized regions (called dyads) where the junctional sarcoplasmic reticulum (jSR) comes into close apposition to the sarcolemma of cardiac myocytes. Previous work has led to the formulation of a model in which the fidelity and strength of EC coupling is critically dependent on the formation of stable dyads where membrane Ca2+ channels activate ryanodine receptors. However, contrary to this view, new evidence obtained by our team shows that the network and junctional SR are highly dynamic. The goal of my project is to elucidate the mechanisms underlying SR motility in ventricular myocytes and discover how these mechanics alter EC coupling in these cells. To do this, we developed a novel strategy to monitor jSR motility in living, acutely dissociated adult ventricular myocytes using viral constructs that allow us to visualize movements of parts of the myocyte that have never been seen in live myocytes before. Our preliminary data are consistent with a model in which the reproducibility of EC coupling results from the activation of a temporally averaged number of SR Ca2+ release units forming and dissolving SR-sarcolemmal junctions. This model represents a departure from long-standing models of Ca2+ signaling in which the T-tubule sarcolemma-SR junction is thought to be static. We will investigate the mechanisms controlling as well as the biogenesis of SR mobility as well as its implications under physiological and pathological conditions. We will test the hypothesis that the SR of adult ventricular myocytes is a dynamic structure capable of forming and dissolving dyads. Furthermore, we will test the hypothesis that changes in the jSR contribute to aberrant Ca2+ signaling seen in myocardial infarction. By elucidating the role of the SR in normal physiology, we will likely uncover a new potential mechanism by which the cell regulates Ca2+ signaling. Studying how the mechanisms controlling SR motility are dysregulated will aid in the understanding of myocardial infarction, heart failure, and other diseases with SR and T-tubule remodeling such as muscular dystrophy. Our expectation is that by providing a mechanism to SR biogenesis and dynamicity, we can discover ways to manipulate the SR to improve disease outcomes.
The project described in this application is designed to challenge the long-standing model that the sarcoplasmic reticulum (SR) is static in cardiac excitation-contraction coupling. We will investigate both the mechanisms controlling SR mobility as well as the implications of this mobility under physiological and pathological conditions. By elucidating the role of SR mobility, we will likely uncover new potential mechanisms by which the cell regulates calcium signaling under normal physiological conditions and determine how these mechanisms are disrupted post-myocardial infarction.
| Li, Lei; Li, Jing; Drum, Benjamin M et al. (2017) Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. Cardiovasc Res 113:147-159 |
| Drum, Benjamin M L; Yuan, Can; Li, Lei et al. (2016) Oxidative stress decreases microtubule growth and stability in ventricular myocytes. J Mol Cell Cardiol 93:32-43 |
| Drum, Benjamin M L; Santana, Luis F (2015) The long and winding road home: how junctin and triadin find their way to the junctional SR. J Mol Cell Cardiol 81:15-7 |
