Catecholamine Interactions with the Cardiac Ryanodine Receptor

PDXScholar Dissertations and Theses Dissertations and Theses Let us know how access to this document benefits you. Abstract The cardiac ryanodine receptor (RyR2) is a Ca 2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca 2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca 2+ flux out of the SR, which results in an overload of intracellular Ca 2+ ; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the β-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca 2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the β-adrenergic receptor, but can also directly inhibit the release of Ca 2+ from RyR2. ii Dedication This thesis is dedicated to my family, who have loved and supported me through my life in both the good and the bad. If it wasn't for them I would not be where I am today.