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. 2024 Dec 26;187(26):7433-7449.e20.
doi: 10.1016/j.cell.2024.11.001. Epub 2024 Dec 3.

Structure-guided design of a peripherally restricted chemogenetic system

Hye Jin Kang  1 , Brian E Krumm  2 , Adrien Tassou  3 , Matan Geron  3 , Jeffrey F DiBerto  2 , Nicholas J Kapolka  2 , Ryan H Gumpper  2 , Kensuke Sakamoto  2 , D Dewran Kocak  2 , Reid H J Olsen  2 , Xi-Ping Huang  4 , Shicheng Zhang  2 , Karen L Huang  3 , Saheem A Zaidi  5 , MyV T Nguyen  5 , Min Jeong Jo  1 , Vsevolod Katritch  5 , Jonathan F Fay  6 , Grégory Scherrer  7 , Bryan L Roth  8
Affiliations

Structure-guided design of a peripherally restricted chemogenetic system

Hye Jin Kang et al. Cell. .

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.

Keywords: GPCR; chemogenetics; peripheral nervous system.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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