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The mammalian orphan nuclear receptors: orphans as cellular guardians

In classical endocrinology, receptors are molecules that bind a hormone or a ligand to transduce signal within a target cell. Later, however, many intracellular receptors have been discovered in mammals, which have not been shown to bind endogenous ligands and are now are referred as “orphan receptors.” The orphan receptors share high degree of structural and functional homology with the classical nuclear receptors (NRs) and are now part of the NR superfamily and therefore referred as orphan nuclear receptors (ONRs). Interestingly, however, ONR members are not evolutionarily or functionally linked and they form a highly diverse group within the NR superfamily. In mammals, ONRs exhibit great functional diversity and majority of them are expressed in a tissue-specific fashion. In the past one decade, functional studies have revealed that they are mediators of multitude of crucial metabolic, developmental, reproductive, and immunological functions in mammals. Emerging studies also indicate the role of ONRs in the onset of several complex human diseases and hence they may be potential candidates for therapeutic drug targeting in the future.