Chemogenetics comprises a recently developed research approach aimed at describing the ways by which engineered biological macromolecules (e.g., hybrid nucleic acids, kinases, enzymes, and receptors) selectively interact with previously unrecognized chemical actuators (e.g., inert and extrinsic drug-like small molecules). Among the various chemogenetic tools recently described, the technology known as DREADDs (designer receptors exclusively activated by designer drugs) has recently emerged as a powerful and widely adopted tool to dissect the contribution of discrete G-protein-coupled receptor (GPCR) signaling pathways in molecularly defined cells to neural function and behavior in preclinical models. In addition to its capacity as a research tool, however, DREADD technology also holds significant promise as a therapeutic platform which may be used to develop innovative clinical therapeutics, such as neuromodulation applications based on remote manipulation of cell type-specific GPCR activity. This chapter will present a brief background relating to the development of DREADD and its history, followed by highlights from recent neuroscience-relevant applications of the technology. Finally, the chapter concludes with an outlook on the potential future of DREADD technology as a clinical tool for treating brain diseases.
G-protein signaling Gi Go Gs Chemogenetics Pharmacogenetics Designer receptors DREADD KORD Kappa opioid receptor Muscarinic receptor hM3Dq hM4Di rM3Ds DREAMM PET MRI GPCR CNS Nonhuman primate CNO Salvinorin-B FDG AgRP GIRK Parkinson’s disease HSV CAV2 AAV RASSL Transgenic animals Viral targeting Synthetic biology Drug discovery
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