Orphan receptors

Orphan receptors are receptors whose natural ligands have not been discovered. Ligands of many receptors which were once considered orphan have now been discovered. Many of these "adopted receptors" have been shown to play critical roles in the cell cycle, metabolism etc., and are often important drug targets.

Traditionally, receptors were discovered when unknown proteins binding to known ligands were identified. However, molecular techniques have now made it possible to identify proteins with unknown function as potential receptors based on their "similarity" to known receptors. This "similarity" may be based on amino acid sequence or on common domains shared by these proteins with known receptors.

All steroid hormones, vitamin D, retinoids, thyroid hormones etc. produce their effects by binding to intracellular receptors. Some receptors are in the cytosol (eg. glucocorticoid receptors), while others are in the nucleus (eg. thyroxine receptor). The ligand (the hormone) diffuses through the cell membrane and binds to its receptor. Once bound, these receptors can bind to specific areas of the DNA, resulting in an increase or decrease the expression of specific genes to which they can bind. Therefore, the receptors of these hormones act as transcription factors. These transcription factors bind to DNA via special domains called DNA binding domains. There are many types of characteristic DNA binding domains which are called zinc finger, leucine zipper, helix-turn-helix, helix-loop-helix etc. Therefore the presence of one of these DNA binding domains is a unique feature of receptors that act as transcription factors.

Molecular biologists use this knowledge to find new intracellular receptors in the cell. Following the completion of the human genome project, they have at their disposal, the sequence of the entire DNA in the human genome. These scientists scan this information to look for proteins that have the characteristic DNA domains. All proteins that are thus identified are potential receptors that act as transcription factors. This approach has been very productive and many previously unknown receptors with critical functions have been identified. A few receptors identified using this technique are PPAR (paroxisome proliferator activated receptor), LXR (liver X receptor), FXR (farnasoid X receptor) and RXR (retinoid X receptor). Many of these receptors had no known function or ligand when they were first discovered. Further research has identified their natural ligands and they have been shown to play fundamental roles in cell functioning. For example, the PPARs have been shown to be important regulators of carbohydrate and lipid metabolism in the cell. Thioglitazones are a group of anti-diabetic drugs that act by binding to the PPAR receptors. In the paper chosen for "Research Article of the Week", the LXR has now been shown to play an important role in mediating glucocorticoid effects in the cell.

Many more orphan receptors are likely to be shown to have important roles in the cell in the near future. Research in this area is particularly interesting because a number of these receptors can be targets for drugs. The PPARs are classical examples for this.