Calcium is the first messenger for the action of thyroid hormone at the level of the plasma membrane: first evidence for an acute effect of thyroid hormone on calcium uptake in the heart.

The thyroid hormone T3 produced a very rapid and transient increase in 45calcium uptake by freshly isolated rat heart slices, which was seen already 15 sec after the addition of the hormone, reached a maximum at 30 sec, and then progressively declined and returned to control values after 10 min. This effect of T3 was independent of extracellular calcium, concentration related (evident at a physiological concentration of 10 pM, reached maximum of about 75% above control at 1 nM, and was smaller at greater concentrations), and thyroid hormone specific, as judged from the order of potency of several thyroid hormone analogs: L-T3 greater than L-T4 greater than or equal to D-T3 greater than 3'-isopropyl-3,5-L-diiodothyronine greater than D-T4 greater than 3,5-L-diiodothyronine greater than r-L-T3 greater than D,L-thyronine. The inorganic calcium channel blockers La3+, Cd2+, and Mn2+ inhibited, in a concentration-related fashion, basal and T3-induced increases in 45Ca uptake in the cardiac slices. The organic calcium channel blockers verapamil, nifedipine, and diltiazem were without effect, indicating that in the quiescent cardiac slice the effect of T3 on 45Ca uptake is independent of sarcolemmal depolarization. Additional studies demonstrated that the stimulatory effect of T3 on 2-deoxyglucose uptake by the cardiac slices required extracellular calcium and was inhibited by the calcium channel blockers La3+, Cd2+, and Mn2+. The present study provides conclusive evidence for two central issues: that calcium is the first messenger for the prompt, plasma membrane-mediated action of thyroid hormone to increase cellular sugar uptake, and that thyroid hormone produces an acute increase in calcium uptake by the heart, an effect that is demonstrable at physiological concentrations and is thyroid hormone specific and, therefore, points to a physiological relevance for this action.