This application seeks support for a project of research directed toward better understanding of the molecular mechanisms and cellular functions of ion transport across human red blood cell membranes. Our investigation of the mechanisms and cellular functions of ion transport seeks to solve four major unsolved problems: first, the mechanisms of lithium transport in human red cells and the regulation of intracellular lithium concentration in red cells from normal persons and from persons with affective disorders including the role of ion pair formation between carbonate and lithium; second, the importance of membrance dipole potential on ion transport in biological membranes and the interactions of membrane cholesterol content and phloretin on red cell ion fluxes; third, the role of calcium mediated potassium leakage and membrane potential in the formation of irreversibly sickled red cells; fourth, the quantitative relationship between transfer of electrical charge and the transfer of neutral ion pairs across red cell membranes. Experiments designed to answer questions relevant to these problems involve observations under various conditions of net and tracer fluxes of anions and alkali cations across red blood cells, red cell ghosts, and bilayer membranes; the electrical properties of thin lipid bilayers; the fusion of cells and fusion of cells to lipid bilayers; analysis of individual cell ion contents using electron probe microanalysis techniques; the determination of fluorescence from dyes added to red cell suspensions; microelectrode measurements of cell membrane potentials.