| First Author | Kang HJ | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 26 | Pages | 7433-7449.e20 |
| PubMed ID | 39631393 | Mgi Jnum | J:360804 |
| Mgi Id | MGI:7791697 | Doi | 10.1016/j.cell.2024.11.001 |
| Citation | Kang HJ, et al. (2024) Structure-guided design of a peripherally restricted chemogenetic system. Cell 187(26):7433-7449.e20 |
| abstractText | 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. |
