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

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. Chemogenetics is a technique for modulating engineered proteins using small molecules. In this Primer, Kang et al. describe the key aspects of designing receptors and small molecules and their use in neuroscience applications.