Retinoic acid is a modulator of thyroid hormone activation of Ca2+-ATPase in the human erythrocyte membrane.

The thyroid hormones thyroxine (T4) and 3,3',5-L-triiodothyronine (T3) stimulate plasma membrane Ca2+-ATPase (EC 3.6.1.3) activity in human erythrocytes by a mechanism independent of the cell nucleus. The current studies were conducted to determine the effect of retinoic acid on the extranuclear activation by T4 and T3 of Ca2+-ATPase in the human red cell. The retinoid inhibited basal and T4-stimulatable activity of that enzyme in a dose-dependent manner. At the highest tested concentration (10(-6) M), retinoic acid inhibited basal enzyme activity by 25% and T4-stimulated activity by 72%. A concentration as low as 5 x 10(-10) M retinoic acid shifted the dose-response curve of both T4 and T3 so that the concentration of each associated with maximal enzyme stimulation was 10(-9) M instead of 10(-10) M. Retinoic acid displaced [125I]T4 binding to red cell membranes as effectively as unlabeled T4. Retinol failed to influence either basal or T4-stimulated enzyme activity or to displace T4 binding. These results indicate that retinoic acid can partially block the T4 and T3 stimulation of Ca2+-ATPase in human red cell membranes and suggest a physiologic role for the retinoid as a modulator of this peripheral action of thyroid hormone. They suggest that the red cell membrane is an important site of action for this active retinoid.