Pathophysiologic control of nuclear triiodothyronine receptor capacity

Mechanisms involved in the reduced T3 receptor capacity found in a variety of pathophysiologic states were investigated by in vitro assessment of T3 receptor-nuclei interaction using tissue prepared from rats. In nuclei from immature animals, nuclear uptake of receptor was reduced, release was accelerated, and these alterations could account for the reduced nuclear receptor capacity. The functions reached the normal adult condition by 30–50 days. Nuclei from animals starved for 72 h showed no change in release of receptor, a 15% decrease in uptake, and 48% decrease in total binding capacity, indicating that the major effect is related to diminished supply of receptor, presumably due to reduced synthesis in the extranuclear compartment. Glucagon administration produced no change in receptor release, 25% decrease in receptor uptake, and nearly equivalent 33% decrease in binding capacity. Alteration in receptor uptake could account largely for changes induced by glucagon. Animals studied 24 h after hepatectomy had a 53% decrease in total binding capacity, but no change in uptake or release, indicating that reduced receptor synthesis is the primary abnormality. Administration of α-amanitin caused a 30% diminution in the binding capacity in the nuclei, without change in uptake and release, and cycloheximide caused an 87% decrease in binding capacity, with minimal change in uptake and no change in release. In both instances the alterations are interpretable as diminished synthesis and availability of receptor, rather than alterations in binding receptor to chromatin. The major cause of diminished receptor capacity appears to be reduced cytosolic synthesis of receptor, with reduction in retention by chromatin-associated factors playing a significant role in immature animals, and during glucagon treatment.