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Chemogenetics integrates chemical reaction and genetic engineering to control  cell physiological activities, which usually utilize genetically engineered macromolecules that interact with specific synthetic molecules. The most widely used molecules include G protein-coupled receptors (GPCRs) and ligand-gated ion channels which are engineered so that instead of their endogenous ligands, they respond to particular small molecules.

Evolutionary timeline of GPCR-based chemogenetic approaches listing the main corresponding tools starting with allele-specific engineered β-adrenergic receptors, RASSLs, and DREADDs. Relevant structures shown include (top) engineered ligands and (bottom) endogenous ligands. Green text indicates no pharmacologic activity at the native target; red indicates activity. Abbreviations: DREADD, designer receptor exclusively activated by designer drug; GPCR, G protein–coupled receptor; RASSL, receptor activated solely by synthetic ligand. (Bryan L.Roth.Annu.Rev.Neurosci.2014)
DREADDs and their downstream intracellular signal transduction pathways.(Deniz Atasoy.Physiol Rev 98: 391–418, 2018)
Chemogenetic Receptor
DREADDs (Designer receptor exclusively activated by designer drug) were engineered from G Protein-Coupled receptors which are relative insensitivity to the endogenous ligandand but could activated by clozapine N-oxide and in turn initiate G-protein signaling cascade and  lead to various physiological changes. Below is a list of representative DREADDs.
DREADD Description Ligand
hM3D(Gq) Increase Ca2+,Activation CNO
hM4D(Gi) Decrease cAMP β/γ-GIRK activation, Inhibitory CNO
KORD Decrease cAMP β/γ-GIRK activation ,Inhibitory SALB
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Schematic overview of how different variants of DREADDs (hM3Dq and hM4Di) can be used to activate and also inhibit groups of neurons (

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1. Pengfei Wei. et al. Processing of visually evoked innate fear by a non-canonical thalamic pathway 
2. Dong S, Rogan SC, Roth BL. Directed molecular evolution of DREADDs: a generic approach to creating next-generation RASSLs. Nat Protoc. 2010 Mar;5(3):561-73
3. Scofield MD, Boger HA, Smith RJ,et al. Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking. Biol Psychiatry. 2015 Oct 1;78(7):441-51.
4. López AJ, Kramár E, Matheos DP,et al. Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation. J Neurosci. 2016 Mar 23;36(12):3588-99.
5. Deniz Atasoy and Scott M. Sternson. CHEMOGENETIC TOOLS FOR CAUSAL CELLULAR AND NEURONAL BIOLOGY.Physiol Rev 98: 391–418, 2018
6. Hyeong-Min Lee, Patrick M. Giguere, and Bryan L. Roth. DREADDs: novel tools for drug discovery and development .2014 April ; 19(4): 469–473.
7. Scott M. Sternson1 and Bryan L. Roth. Chemogenetic Tools toInterrogate Brain Functions .Annu. Rev. Neurosci. 2014. 37:387–407.

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