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),[1] and not to their natural ligand(s). RASSL's represent a GPCR-based chemogenetic tool.
Mechanism
RASSLs and DREADDs are families 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. Viral expression of DREADD proteins, both in-vivo enhancers and inhibitors of neuronal function, have been used to bidirectionally control behaviors in mice (e.g odor discrimination).[2]
History
Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound[3] 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.[4]
References
- ↑ Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL (March 2007). "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 of the United States of America. 104 (12): 5163–8. doi:10.1073/pnas.0700293104. PMC 1829280. PMID 17360345.
- ↑ Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC (July 2015). "Differential Muscarinic Modulation in the Olfactory Bulb". The Journal of Neuroscience. 35 (30): 10773–85. doi:10.1523/JNEUROSCI.0099-15.2015. PMC 4518052. PMID 26224860.
- ↑ Coward P, Wada HG, Falk MS, Chan SD, Meng F, Akil H, Conklin BR (January 1998). "Controlling signaling with a specifically designed Gi-coupled receptor". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 352–7. doi:10.1073/pnas.95.1.352. JSTOR 44466. PMC 18222. PMID 9419379.
- ↑ Mueller KL, Hoon MA, Erlenbach I, Chandrashekar J, Zuker CS, Ryba NJ (March 2005). "The receptors and coding logic for bitter taste". Nature. 434 (7030): 225–9. doi:10.1038/nature03352. PMID 15759003.
Further reading
- Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, et al. (August 2008). "Engineering GPCR signaling pathways with RASSLs". Nature Methods. 5 (8): 673–8. doi:10.1038/nmeth.1232. PMC 2703467. PMID 18668035.