Abstract
Chemogenetics is an approach for engineering proteins to enable their modulation by otherwise inert small molecules. Although kinases, enzymes and ion channels have been used for chemogenetics, the most widely used platform is based on G protein-coupled receptors (GPCRs), using designer receptors exclusively activated by designer drugs (DREADDs). DREADDs have been used ubiquitously to modulate cellular signalling and neuronal activity and are a key technology for modern causal neuroscience. Here we provide a Primer on key aspects of DREADD technology, emphasizing how to reliably design and validate chemogenetic transducers and actuators. We also provide recommendations for the use of DREADDs for specialized applications including modulating metabolically essential peripheral tissues and distinct neuronal populations in non-human primates.
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Acknowledgements
Work in the Roth laboratory is supported by grants from the NIH. J.W. was supported by funds from the NIDDK Intramural Research Program (Bethesda, MD, USA). This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. 2022R1C1C1008786). T.M. was supported by the Japan Agency for Medical Research and Development (JP18dm0307007).
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Introduction (H.J.K., T.M., J.W. and B.L.R.); Experimentation (H.J.K., T.M., J.W. and B.L.R.); Results (H.J.K., T.M., J.W. and B.L.R.); Applications (H.J.K., T.M., J.W. and B.L.R.); Reproducibility and data deposition (H.J.K., T.M., J.W. and B.L.R.); Limitations and optimizations (H.J.K., T.M., J.W. and B.L.R.); Outlook (H.J.K., T.M., J.W. and B.L.R.); Overview of the Primer (B.L.R.).
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B.L.R. is an SAB member of Onsero, Epiodyne, Escient and Septerna Pharmaceuticals and is listed as an inventor on patents related to the TRUPATH technology. The other authors declare no competing interests.
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Glossary
- Chemogenetic actuator
-
The ligand activating the designer receptor exclusively activated by designer drug.
- Chemogenetic transducer
-
The receptor construct.
- Codon optimization
-
Experimental approaches designed to improve the codon composition of a recombinant gene without altering the amino acid sequence.
- Kinome
-
A collection of entire kinases.
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Kang, H.J., Minamimoto, T., Wess, J. et al. Chemogenetics for cell-type-specific modulation of signalling and neuronal activity. Nat Rev Methods Primers 3, 93 (2023). https://doi.org/10.1038/s43586-023-00276-1
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DOI: https://doi.org/10.1038/s43586-023-00276-1