HORMONAL REGULATION OF GROWTH AND DIFFERENTIATION

In this continuing research project the hormonal regulation of ion fluxes in target tissues will be further examined with particular reference to the stimulation of active Na,K transport by thyroid hormone and the mechanism of the associated hormonal induction of Na,K-ATPase. Although previous studies have been restricted to examining these effects in isolated tissues from animals treated with thyroid hormone or in cells in primary culture, we have recently characterized two continuous liver cell lines that respond to triiodothyronine (T3) in vitro with a substantial stimulation of active Na,K transport, an induction of the Na,K-ATPase, and an enhancement of glucose uptake and lactate production. Studies employing these cells have confirmed the hypothesis - proposed at the end of the preceding project period - that, rather than reflecting a primary induction of the Na,K-ATPase itself, the stimulation of active Na,K transport by T3 is attributable to a hormonally induced increase in the passive permeability of target- cell membranes with a concomitant facilitation of rate-limiting passive fluxes of sodium and potassium in directions opposite to their active transport. Major objectives during the next project period will include 1) identification and characterization of these specific hormone-responsive passive flux pathways; 2) an exploration of the mechanism by which thyroid hormone additionally stimulates glucose entry; 3) a quantitative examination of relationships between Na,K pump activity, lactate production, and metabolic energy consumption in control and T3- treated cells; 4) an examination of the postulate that the increase in Na,K-ATPase following exposure to T3 reflects an adaptive cellular response to the hormonally induced increase in passive cation leaks rather than a direct effect of thyroid hormone itself; and 5) a characterization of possible functional differences in skeletal muscle Na,K-ATPase isozymes which exhibit marked differences in ouabain sensitivity, and which we have recently shown to be differentially induced by thyroid hormone in vivo. The results of these studies should lead to a better understanding of mechanisms by which thyroid hormone stimulates passive and active Na,K transport and Na,K-ATPase enzymatic activity in target tissues, and should provide further clarification of the role of hormonally induced changes in ion fluxes in the regulation of cellular metabolic rate and the mediation of other endocrine responses.