A New Tool to Study the DREADDed Peripheral Nervous System

A groundbreaking advancement in studying the peripheral nervous system (PNS) has emerged through the development of a new chemogenetic tool. The PNS plays a crucial role in regulating vital processes like digestion, secretion, pancreatic function, liver metabolism, and visceral pain signaling. Precision tools are essential for understanding PNS activity and designing therapies for disorders involving the gut–nerve interface. While Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have been widely used in the central nervous system (CNS), their application in the PNS has faced challenges due to off-target effects and activation limitations.

Kang et al. addressed these issues by re-engineering the hydroxycarboxylic acid receptor 2 (HCAD2), a Gαi-coupled receptor predominantly expressed in peripheral nerves, into a PNS-specific DREADD. Using cryogenic electron microscopy (cryo-EM), the team designed a selective actuator molecule, FCH, tailored to activate HCAD2 without crossing the blood–brain barrier. This innovation ensures peripheral specificity, avoiding central side effects. Experimental validation in mouse models demonstrated that FCH administration suppressed neural activation and reduced acute and chronic pain responses caused by mechanical, heat, and inflammatory stimuli.

This system provides a precise tool for studying PNS-driven processes such as digestion, metabolism, and gut–brain communication while offering therapeutic potential for visceral pain, metabolic regulation, and gastrointestinal motility disorders. Despite challenges like ensuring receptor inertness without ligand exposure and minimizing off-target effects, this platform marks a significant leap in expanding chemogenetic tools beyond the brain, paving the way for targeted treatments of PNS-related diseases.