The studies proposed in this application are aimed at obtaining a more complete understanding of the regulation of cellular cation transport by thyroid hormone. In particular the applicant has proposed, and begun to test, the hypothesis that the known stimulation of active sodium and potassium transport by thyroid hormone, rather than being attributable to a primary induction of the Na, K pump (Na,K-ATPase) as has previously been postulated, instead is the result of a more proximal hormonal enhancement of the passive leak of sodium and/or potassium across the cell membrane. Initial studies by the applicant have lent support to this hypothesis by demonstrating not only that in vivo thyroid hormone treatment does indeed increase passive potassium efflux from both isolated rat diaphragm and liver slices, but furthermore that this effect is present as early as 6 hours after an injection of T3, and substantially precedes any induction of the Na,K-ATPase itself. Further investigations of the effects of in vivo thyroid hormone treatment on cation transport in rat liver slices are proposed to better characterize this hormonal stimulation of passive potassium efflux. Additional studies in cultured cells (primarily rat hepatocytes) will examine the direct in vitro effect of thyroid hormone on both the passive fluxes and intracellular concentrations of sodium and potassium, the role of passive cation fluxes in mediating the stimulation of active cation transport by thyroid hormone, and the relationship of T3-induced changes in passive and active cation fluxes to the number of Na,K pumps. It is hoped that these detailed investigations will additionally lead to a better understanding of the possible role of changes in cation fluxes in mediating thyroid hormone action.
