The purpose of this project is to understand the properties and the regulation of the voltage-dependent charge movement (gating current) which governs the function of cardiac Na+, and Ca++ channels. The relationship of charge movement to the processes of activation and inactivation of the Na+ and Ca++ ionic currents will be studied. The effects of agents which are known to enhance or reduce the Ca++ channel currents will be examined for their effects on Ca++ channel charge movement. The experiments will be conducted using the cultured embryonic chick myocyte preparation, which has little or no T-tubules. Single cells will be voltage-clamped using the whole cell patch clamp configuration. Ionic currents will be blocked using appropriate intra- and extracellular solutions, and linear capacitive currents will be subtracted (P/-5 protocol). The residual current is the non-linear charge movement (gating current). Na+ and Ca++ channel gating currents will be separated by differences in their kinetics and voltage-dependence. In addition to gaining further understanding of the basic mechanisms of voltage-dependent gating of cardiac Na+ and Ca++ channels, this study will provide new information concerning the actions of channel regulatory and modulatory agents on the gating currents. Preliminary data suggests that endogenous regulatory agents as well as therapeutic agents exert their effects, at least in part, through actions on the Ca++ channel gating curtents. Thus, a knowledge of the mechanism of action of these agents on the gating currents is crucial to an understanding of Ca++ channel regulation, in normal and diseased states.
|Josephson, I R (1997) Kinetic components of the gating currents of human cardiac L-type Ca2+ channels. Pflugers Arch 433:321-9|
|Josephson, I R; Varadi, G (1996) The beta subunit increases Ca2+ currents and gating charge movements of human cardiac L-type Ca2+ channels. Biophys J 70:1285-93|
|Josephson, I R; Cui, Y (1995) Cardiac channel gating charge movements: recovery from inactivation. Pflugers Arch 430:682-9|
|Josephson, I R; Cui, Y (1994) Voltage- and concentration-dependent effects of lidocaine on cardiac Na channel gating charge movements. Pflugers Arch 428:485-91|
|Josephson, I R; Sperelakis, N (1992) Kinetic and steady-state properties of Na+ channel and Ca2+ channel charge movements in ventricular myocytes of embryonic chick heart. J Gen Physiol 100:195-216|