Receptor activated solely by a synthetic ligand

A receptor activated solely by a synthetic ligand (RASSL) or Designer Receptor Exclusively Activated by Designer Drugs (DREADD), permits spatial and temporal control of G protein signaling in vivo. These systems utilize G protein-coupled receptors (GPCR) engineered to respond exclusively to synthetic small molecules ligands, like clozapine N-oxide (CNO), and not to their natural ligand(s). RASSL's represent a GPCR-based chemogenetic tool.

Mechanism

RASSLs and DREADDs are a family of designer G-protein-coupled receptors (GPCRs) built specifically to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called RASSLs (receptors activated solely by synthetic ligands), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (Gs, Gi, Gq). A major cause for success of RASSL resources has been open exchange of DNA constructs, and RASSL related resources.

Uses

GPCRs are the target for some of the most widely used pharmaceuticals to treat diseases that involve virtually all tissues of the body. New GPCR signaling systems will provide insights into GPCR-induced physiological responses and will allow for new forms of controlling engineered tissues in vivo.

History

Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound^[1] and the concept for RASSLs was first published in 1998.^[2] and has gradually been gaining momentum. The first international RASSL meeting was scheduled for April 6, 2006. A simple example of the use of a RASSL system in behavioral genetics was illustrated by Mueller et al. (2005) where they showed that expressing a RASSL receptor in sweet taste cells of the mouse tongue led to a strong preference for oral consumption of the synthetic ligand, whereas expressing the RASSL in bitter taste cells caused dramatic taste aversion for the same compound.^[3]

Bibliography

• Armbruster, B. N., X. Li, M. H. Pausch, S. Herlitze, and B. L. Roth (2007). "From the Cover: Evolving the Lock to Fit the Key to Create a Family of G Protein-coupled Receptors Potently Activated by an Inert Ligand.". Proceedings of the National Academy of Sciences 104 (12): 5163–168. doi:10.1073/pnas.0700293104. PMC 1829280. PMID 17360345. 
• Conklin, Bruce R., Edward C. Hsiao, Sylvie Claeysen, Aline Dumuis, Supriya Srinivasan, John R. Forsayeth, Jean-Marc Guettier, W. C. Chang, Ying Pei, Ken D. McCarthy, Robert A. Nissenson, Jürgen Wess, Joël Bockaert, and Bryan L. Roth. "Engineering GPCR Signaling Pathways with RASSLs." Nature Methods 5.8 (2008): 673-78. Web. 28 Nov. 2012. <http://www.ncbi.nlm.nih.gov/pubmed/18668035>.

References