Retinoic Acid Actions through Mammalian Nuclear Receptors

The retinoic acid receptors (RARs) and retinoid X receptors are among the most intensely studied nuclear hormone receptors. The six mammalian nuclear receptors for retinoids are encoded by distinct genes. Retinol oxidization to retinaldehyde occurs through enzymes in two classes, the cytosolic alcohol dehydrogenases (ADHs) and the microsomal short-chain dehydrogenases/reductases. There are various forms of retinoid-binding proteins in cells, some of which are in intracellular compartments while others carry the retinoids in the extracellular environment. Without knowing all the physical connections in these complexes, it is difficult to develop synthetic ligands that may act allosterically, by binding to one domain in the protein complex but inducing a functional change in another domain of the receptor. A better structural understanding of NR coactivators or corepressors is also required in the field. The dynamic expression of these retinoid receptors throughout different stages of development considerably suggests that we should now move beyond ligand binding.