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A receptor activated solely by a synthetic ligand (RASSL) or designer receptor exclusively activated by designer drugs (DREADD), is a class of chemogentically-engineered proteins that permit spatial and temporal control of G protein signaling in vivo. Originally differentiated by the approach used to engineer them, RASSLs and DREADDs are often used interchangeably now to represent an engineered G-protein receptor-ligand system. These systems utilize G protein-coupled receptors (GPCR) engineered to respond exclusively to synthetic ligands, like clozapine N-oxide (CNO), rather than to their natural ligand(s).

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, DREADDs exist to interrogate several GPCR signaling pathways, including those activated by Gs, Gi, Gq, Golf, and β-arrestin. A major cause for success of RASSL resources has been open exchange of DNA constructs, and RASSL related resources.

The hM4Di-DREADD's inhibitory effects are a result of the CNO's stimulation and resulting activation of the G-protein inwardly rectifying potassium (GIRK) channels. This causes hyperpolarization of the targeted neuronal cell and thus attenuates subsequent activity.

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 evaluate behaviors in mice and rats. Due to their ability to modulate neuronal functions, DREADDs are used as a tool to evaluate both the neuronal pathways and behaviors associated with drug-cues and drug addiction.

History
Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound 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. The attenuating effects of the hM4Di-DREADD were originally explored in 2007, before being confirmed in 2014.