Thyroid hormone nuclear receptors and their role in the metabolic action of the hormone

Abstract

Thyroid hormone nuclear receptor molecules have been characterized as proteins of approximately 49 000 molecular weight existing in cells attached to chromatin and with 4000–8000 copies per nucleus. They bind T 3 with K a of 0.2 × 10 10 l/mol and show microheterogeneity on isoelectric focusing. Hormone responsiveness varies with receptor content in the nucleus and occupancy of receptor by T 3. Recent investigations have shown that the receptors are part of the v-erbA related super family of nuclear hormone receptors. At least two types of T 3 receptors (TR) exist, one coded by a gene on chromosome 3 (TRβ) and a second coded on chromosome 17 (hTRα). Receptors are low in the fetus and, in the adult, are dramatically reduced by starvation, illness and glucagon. Receptors function through binding of T 3 or other hormone analogs to a domain in the carboxyl portion of the protein, and binding of the receptor–T 3 complex through ‘DNA-fingers’ to specific response elements as enhancers and located in the 5′-flanking DNA of thyroid hormone responsive genes. Extensive studies on regulation of rat growth hormone have suggested binding of receptor or associated factors to several positions in the 5′-flanking DNA, and recent studies suggest that a crucial area may be a 15 bp segment between bases −179 and −164. Abnormal receptors are believed to be responsible for the syndrome of generalized resistance to thyroid hormone action, but it is yet unclear as to which form (or forms) of the receptor is abnormal in this syndrome.