Chemogenetic

Chemogenetics is a set of methods that allows selective control of cellular activity through engineered proteins that respond to designed small molecules. By introducing gene-encoded receptors or ion channels into cells, researchers can activate or inhibit those cells with systemically administered ligands that are otherwise inert.

The most widely used chemogenetic tools are designer receptors exclusively activated by designer drugs (DREADDs), which are modified G protein–coupled receptors that trigger defined intracellular signaling when bound by a ligand. Another family, PSAMs with PSEMs, uses ligand-gated ion channels to control membrane potential. The ligands are chosen to have limited activity on native receptors.

Historically, DREADDs gained prominence in neuroscience in the late 2000s. Clozapine-N-oxide (CNO) was commonly used as the activating ligand, but later studies raised concerns about metabolic conversion to clozapine and off-target effects. This has spurred the development of alternative ligands with better pharmacokinetic properties and reduced off-target actions.

Applications span basic neuroscience to study circuits and behavior, metabolism, and disease models in animals. Chemogenetic approaches enable temporal control of specific cell populations without requiring light delivery, complementing optogenetics. They also hold potential for therapeutic strategies, provided safe and robust delivery and regulation can be demonstrated.

Limitations include variability in receptor expression levels, ligand pharmacology, and potential immune responses to viral vectors. Off-target effects, slow onset or washout compared with optogenetics, and translational hurdles to humans pose ongoing challenges. Researchers continue to improve receptor designs and ligands and to refine targeting, dosing, and safety assessments. Ethical considerations address gene delivery and long-term effects.