Steroid receptor isoforms: exception or rule?

Since the first steroid receptor was cloned, it was quickly identified as one of many such receptors constituting a gene superfamily which has grown to include not only steroid receptors but also receptors for thyroid hormone, retinoic acid, 1,25-dihydroxyvitamin D3 as well as a number of less traditional ligands, including farnesoids and fatty acids. Interestingly, these receptors are far outnumbered by the 'orphan' receptors for which ligands are still being sought. The original cloning of nuclear receptors, although sometimes identifying more than one receptor form, led to the general premise that each ligand has its cognate receptor through which signal is transduced to the transcriptional machinery. Regulation of this process was found to occur at the level of receptor expression, ligand availability, and more recently, through post-translational modifications of the receptor and interaction of a variety of coactivators/corepressors with the receptor protein. The continuing identification of more than a single form for many of the receptors directed the attention of a number of investigators toward defining possible roles for these 'extras'. This review examines the different forms of nuclear receptor gene family members and how they may provide an additional level of regulation.