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.
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.
GPCRs are the target for some of the most widely used pharmaceuticals to treat diseases that involve virtually all[vague] 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).
Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound and the concept for RASSLs was first published in 1998. 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.
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- Mueller, Ken L.; Hoon, Mark A.; Erlenbach, Isolde; Chandrashekar, Jayaram; Zuker, Charles S.; Ryba, Nicholas J. P. (10 March 2005). "The receptors and coding logic for bitter taste". Nature. 434 (7030): 225–229. doi:10.1038/nature03352. PMID 15759003.