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Related Experiment Video

Updated: Jun 5, 2025

Chemogenetic Regulation in Reprogrammed Stem Cell-derived Precursor Cells in Treating Neurodegenerative Diseases

Chemogenetic Regulation in Reprogrammed Stem Cell-derived Precursor Cells in Treating Neurodegenerative Diseases

Published on: May 2, 2025

Structure-guided design of a peripherally restricted chemogenetic system.

Hye Jin Kang¹, Brian E Krumm², Adrien Tassou³

¹Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

|December 4, 2024

Summary

A new designer receptor exclusively activated by designer drugs (DREADD), called HCAD, enables precise control of peripheral systems. This chemogenetic tool effectively reduces pain without impacting the central nervous system.

Keywords:

GPCR chemogenetics peripheral nervous system

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Published on: December 22, 2020

Area of Science:

Neuroscience
Pharmacology
Biochemistry

Background:

Designer receptors exclusively activated by designer drugs (DREADDs) are vital chemogenetic tools for controlling cellular functions.
Existing DREADDs may have limitations in targeting specific systems due to blood-brain barrier (BBB) penetration.

Purpose of the Study:

To develop a peripherally restricted DREADD system for precise control of peripheral signaling.
To create a novel chemogenetic tool that minimizes central nervous system (CNS) effects.

Main Methods:

Structure-guided design and mutagenesis to create hydroxycarboxylic acid receptor DREADD (HCAD).
Utilized an ultra-large make-on-demand library for analoging and identified a BBB-impermeable chemical actuator.
Determined HCAD structure via cryo-electron microscopy (cryo-EM) and validated its function in dorsal root ganglion (DRG) neurons.

Main Results:

Developed HCAD, a peripherally restricted Gi-DREADD with minimal native brain expression.
HCAD activation in DRG neurons inhibited action potential firing.
Demonstrated reduction in both acute and inflammatory pain models.

Conclusions:

The HCAD system offers a novel method for studying peripheral systems with reduced CNS side effects.
This structure-guided approach can accelerate the development of future chemogenetic tools for research and therapeutic applications.