The applicant has identified a new potassium channel gene (Kv4.3) that is expressed at high levels in canine and human ventricle. Based on mRNA expression studies and analysis of the functional properties of the transient outward current (Ito) in ventricular myocytes he has suggested that the Kv4.3 channel is the major channel underlying the Ito in canine and human myocytes. This channel is an important determinant of regional differences in the duration and shape of the cardiac action potential, which contribute to such fundamental phenomena as the configuration of the ST segment and the T wave in the electrocardiogram. It is also likely to be of considerable importance for understanding the actions and interactions of antiarrhythmic drugs. The applicant will intensively study the function and distribution of this channel in canine heart. He also will study the distribution of other potassium channel genes in canine heart with a view to gaining insight into which potassium channel genes contribute to the regional differentiation of the cardiac action potential.
The specific aims are: 1) Compare the biophysical and pharmacological properties of the Kv4.3 channel with the native transient outward current (Ito) in canine heart to test the hypothesis that the Kv4.3 alpha subunit can, by itself, reproduce the function of the native current. 2) Examine the distribution of Kv4.3 channel protein expression in canine heart. 3) Examine potassium channel gene expression in different specialized regions of canine heart to determine the molecular basis for different action potential waveforms in these tissues.
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