Retinoic Acid-related Orphan Receptors

Retinoic acid-related Orphan Receptors (RORs) are a family of orphan nuclear receptors that are believed to play a role in numerous physiological processes, including circadian rhythm and bone metabolism. The endogenous ligand for these receptors is not yet known.

Three members of the ROR family have been identified: RORα, RORβ and RORγ. RORα shows the highest expression levels in the cerebellum and thalamus, whilst RORβ is expressed in a more restricted fashion in the brain and retina. RORγ isoforms are expressed in a number of tissues, with the RORγ2 isoform being exclusively expressed in a number of immune cell types.

The expression of RORs correlates with their roles in different physiological functions. For example, RORα regulates Purkinje cell gene expression, thereby influencing Purkinje cell maturation. RORβ is crucial for rod development in the retina, and RORβ-deficient mice exhibit postnatal retinal degeneration. Mice deficient in either RORα or RORβ also exhibit abnormalities in circadian behavior.

The involvement of RORs in circadian rhythms is a consequence of their binding to ROR DNA response elements (ROREs). These elements are also bound by Rev-Erbα and Rev-Erbβ. Cross-talk between these nuclear receptor families is particularly evident when considering the expression of Bmal1, a key circadian 'clock gene' that contains two ROREs in its promoter. RORs upregulate Bmal1 expression whilst Rev-Erbs repress transcription. Bmal1/Clock or Bmal1/Npas2 heterodimers bind to promoters encoding Rev-Erbα and RORα, enhancing their expression and thus constituting a positive feedback loop. The Bmal1/Clock complex also binds to the promoters of Period (Per) and Cryptochrome (Cry) genes, which in turn inhibit Bmal1/Clock and Bmal1/Npas2 complexes. These loops of gene expression are responsible for generating circadian rhythms.

External sources of pharmacological information for Retinoic Acid-related Orphan Receptors :

• IUPHAR Receptor Code

• BJP Guide

Retinoic Acid-related Orphan Receptor Gene Data