The long term goals of this project are to understand the basis of pacemaker activity in cardiac tissues. As a first step towards this gal we will investigate the distribution, regulation, heterogeneity of properties and structure of the i/f channel. We have recently demonstrated the existence of the i/f current in mammalian ventricular monocytes at non- physiologic potentials, and others have demonstrated its presence in pathologic conditions in the normal diastolic potential range. Given these observations we plan to use biophysical techniques (permeabilized patch, whole cell, single channel and pulled off patch recording) to study the properties of i/f in SA node, atrium, Purkinje endocardium, mid-myocardium and epicardium. We will look carefully for differences in biophysical properties and mechanisms of regulation (some of which have already been observed) to develop a profile of i/f in each cardiac tissue type. These studies should help in the development of a selective pharmacology for i/f in different cardiac regions. We will also study the regulation of i/f in sinus node in more detail. In particular we will expand on our recent observations demonstrating regulation of i/f, voltage dependence and conductance by serine-threonine kinases as well as tyrosine kinases. We will attempt to further define the pathways through which these effects are exerted and the net result will attempt to further define the pathways through which these effects are exerted and the net result these treatments have on i/f at the single channel level. Finally, the study of any ion channel is greatly facilitated by a knowledge of the channel structure. Our last aim is to apply modern techniques (PCR, expression and suppression clothing) in a concerned attempt to obtain a clone of the i/f channel. Taken together these studies of the distribution, modulation and structure of i/f should greatly enhance our knowledge of this important cardiac channel, as well as hopefully provide new approaches to the treatment of disturbances of cardiac rhythm.
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