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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.[1] 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.[2] These systems utilize G protein-coupled receptors (GPCR) engineered to respond exclusively to synthetic ligands, like clozapine N-oxide (CNO),[3] rather than to their natural ligand(s).
Mechanism[edit]
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.[4] 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. [5]
Uses[edit]
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 evaluate behaviors in mice and rats.[6] 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. [7]
History[edit]
Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound[8] 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.[9] The attenuating effects of the hM4Di-DREADD were originally explored in 2007, before being confirmed in 2014.[5]
- ^ Roth BL (February 2016). "DREADDs for Neuroscientists". Neuron. 89 (4): 683–94. doi:10.1016/j.neuron.2016.01.040. PMC 4759656. PMID 26889809.
- ^ Conklin, Bruce R; Hsiao, Edward C; Claeysen, Sylvie; Dumuis, Aline; Srinivasan, Supriya; Forsayeth, John R; Guettier, Jean-Marc; Chang, W C; Pei, Ying (August 2008). "Engineering GPCR signaling pathways with RASSLs". Nature Methods. 5 (8): 673–678. doi:10.1038/nmeth.1232. ISSN 1548-7091. PMC 2703467. PMID 18668035.
{{cite journal}}: CS1 maint: PMC format (link) - ^ 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.
- ^ Urban, Daniel J.; Roth, Bryan L. (2015-01-06). "DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility". Annual Review of Pharmacology and Toxicology. 55 (1): 399–417. doi:10.1146/annurev-pharmtox-010814-124803. ISSN 0362-1642.
- ^ a b Zhu, Hu; Roth, Bryan L. (May 2014). "Silencing Synapses with DREADDs". Neuron. 82 (4): 723–725. doi:10.1016/j.neuron.2014.05.002. ISSN 0896-6273. PMC 4109642. PMID 24853931.
{{cite journal}}: no-break space character in|first2=at position 6 (help)CS1 maint: PMC format (link) - ^ 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.
- ^ Ferguson, Susan M.; Eskenazi, Daniel; Ishikawa, Masago; Wanat, Matthew J.; Phillips, Paul E. M.; Dong, Yan; Roth, Bryan L.; Neumaier, John F. (January 2011). "Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization". Nature Neuroscience. 14 (1): 22–24. doi:10.1038/nn.2703. ISSN 1546-1726. PMC 3058296. PMID 21131952.
{{cite journal}}: CS1 maint: PMC format (link) - ^ 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.