The Na/K pump is an important membrane protein which has been extensively studied biochemically , physiologically, pharmacologically and biophysically. The Na/K pump is responsible for maintaining ion gradients across the cell membrane. In the heart, the Na/K pump is also important clinically for the inotropic and chronotropic actions produced by pharmacological or physiological alterations in Na/K pump activity. Despite this, the detailed mechanism of the Na/K pump is still elusive. The long range goal of this research is to understand how the Na/K pump: 1) is physiologically regulated in its activity, sensitivity to cardiac glycosides and site danger; 2) is regulate pathophysiologically (e.g. ischemia and congestive heart failure); and 3)is involved in the regulation of electrical and mechanical activity in the heart. This study will focus on the definition and utilization of a computer model to predict the behavior of the Na/K pump under a wide range of conditions, especially physiologically and clinically relevant conditions. A principle goal of this study will be to bring the biochemical information available on the Na/K pump to aid of physiological and biophysical experimentation. This work will provide a better understanding of Na/K pump function and should lead to new insights into the role of the Na/K pump in cardiac function. This proposal will complement ongoing research in this laboratory by incorporating into the model, data produced in experimental studies on the ionic and voltage dependence of Na/K pump activity as measured with the whole-cell patch-clamp technique in isolated myocytes. This study will utilize these experimental results, as well as published results from other laboratories, to construct a model of the Na/K pump. This model will incorporate the known biochemical data of a multistate cyclic enzyme and physiological and biophysical data on the regulation of Na/K pump function and glycoside sensitivity. The completion of the specific aims of this project will advance our understanding of Na/K pump function and provide new insight into its role in cardiac physiology.
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