ANGIOTENSIN II AND CARDIAC G PROTEIN COUPLED ION CHANNEL

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The cellular mechanisms which underlie the inotropic and chronotropic effects of ANG II in heart are not well understood; however, ion channels clearly play critical roles in the regulation of cardiac output through contractility and heart rate. There is increasing evidence that ANG II has acute effects on the electrophysiology of the heart, and the clinically beneficial effects of modulating the renin-angiotensin system are well known. It is not yet clear how these two observations are related. The specific goals of this proposal are to characterize the acute effects of ANG II on cardiac Ca2+ channels and delayed rectifier K+ channels, two important modulators of cardiac contractility, and to examine the receptor-G protein signaling pathways utilized by ANG II receptors in heart. To address these questions we will use cardiac-like cells derived by in vitro differentiation from mouse embryonic stem (ES) cells. This tissue culture model offers a number of advantages over studies of primary cardiocyte cultures. Most importantly, we have generated a panel of mutant ES cells with targeted inactivation of specific G protein alpha subunits. Once the electrophysiological responses are characterized and the ANG II receptor subtypes responsible for each channel identified, we will use these alpha subunit null cells to identify G proteins required for signaling to each effector. The studies outlined in this proposal are the critical first step in understanding how the acute effects of ANG II on cardiac electrophysiology relate to normal cardiac function and how this system is altered in pathologic states.