Thyroid Hormone Receptors: Multiple Forms, Multiple Possibilities*

THE biological importance of the thyroid gland has been recognized for centuries (1). The realization in the late 19th century that cretinism and myxedema result from loss of thyroid function led to the discovery of T4 (2) and T3 (3) as the predominant and most potent thyroid hormones, respectively. During the ensuing decades the plasma membrane (4), synapse (5), endoplasmic reticulum (6), and mitochondria (7) have all been considered as potential cellular sites of action of the thyroid hormones. In the 1960s, however, it was noted that many of the physiological actions of T3 were preceded by nuclear RNA transcription (8, 9), and high-affinity nuclear receptors for T3 were discovered soon thereafter (10,11). The specificity of the nuclear T3 receptors (TRs) for thyroid hormone analogs closely parallels the biological potency of the compounds (12, 13), and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T3 in most cases (14, 15). Thus, although thyroid hormones may have some important nonnuclear actions, the concept that the majority of the actions of T3 are mediated by nuclear TRs was generally accepted by the mid-1980s (16, 17). The discovery of multiple TR isoforms and the characterization of their structure, regulation, properties, and function are the subjects of this review.