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Chemogenetics for cell-type-specific modulation of signalling and neuronal activity

Nature Reviews Methods Primers volume 3, Article number: 93 (2023) Cite this article

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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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Fig. 1: Chemogenetics developments over time.
Fig. 2: Signalling pathways and subsequent neuronal modulation by typical designer receptor exclusively activated by designer drugs.
Fig. 3: Characterization of G protein selectivity.
Fig. 4: Chemogenetic actuators differ in on-target and off-target activities.
Fig. 5: Recommended strategy for profiling new chemogenetic actuators.
Fig. 6: DREADD expression in a cell-type-specific fashion.
Fig. 7: PET imaging for validation of designer receptors exclusively activated by designer drug expression and function in vivo.

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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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Authors and Affiliations

  1. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea

    Hye Jin Kang

  2. Department of Biological Science, Sungkyunkwan University, Suwon, South Korea

    Hye Jin Kang

  3. Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, Japan

    Takafumi Minamimoto

  4. Molecular Signaling Section, NIDDK, NIH, Bethesda, MD, USA

    Jürgen Wess

  5. Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Bryan L. Roth

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  1. Hye Jin Kang
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  2. Takafumi Minamimoto
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  3. Jürgen Wess
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  4. Bryan L. Roth
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Contributions

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.).

Corresponding authors

Correspondence to Hye Jin Kang or Bryan L. Roth.

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Competing interests

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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Nature Reviews Methods Primers thanks S. Kiyonaka, J. Neumaier, C. Price and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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