MOLECULAR TARGETING OF CA2+ AND K+ CHANNELS IN HEART

Description (Adapted from Applicant's Abstract) The overall goal of the research proposed in this project is to identify molecular properties of cardiac ion channel proteins and organic drug molecules that will allow targeted control of calcium entry in cardiac myocytes in general and in myocytes surviving in the border zone of infarcted hearts in particular. Motivation for this goal comes from data in other projects of this program where it was shown that increasing L-type calcium channel current may prevent reentrant tachycardia in the infarcted canine heart, and that functional and molecular properties of key ion channels (Na+, Ca2+, and K+) are altered in epicardial cells that survive in the epicardial border zone (EBZ) of infarcted hearts. The overall goal of this project is thus to provide molecular insight into mechanisms that would permit more precise targeting of drugs to control calcium entry in these cells. There are thus three specific aims of this project. (1) to identify molecular determinants that target potentiation of calcium entry to cardiac vs. smooth muscle L-type calcium channels: (2) to test the hypothesis that drug-induced changes in L-type Ca2+ channel deactivation kinetics is a powerful mechanism of modulating calcium entry into targeted cells; and (3) to test the hypothesis that subunit assembly of 1Ks channel, which may differ between normal and EBZ cells, confers unique pharmacological and regulatory properties upon expressed channels. Together this information will provide a molecular basis for targeting control of calcium entry into cells of the EBZ which, in combination with the data obtained from other Projects of this program will provide the framework for the development of novel anti-arrhythmic therapy to control reentrant arrhythmias in ischemia.