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  3. Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

  • Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):E1996-E2005. doi: 10.1073/pnas.1615255114.
Zhe Li 1,  Pang-Yen Tseng 1,  Vinod Tiwari 2,  Qian Xu 1,  Shao-Qiu He 2,  Yan Wang 1,  Qin Zheng 1,  Liang Han 1,  Zhiping Wu 3 4,  Anna L Blobaum 5,  Yiyuan Cui 6,  Vineeta Tiwari 2,  Shuohao Sun 1,  Yingying Cheng 1,  Julie H Y Huang-Lionnet 2,  Yixun Geng 1,  Bo Xiao 6,  Junmin Peng 3 4 7,  Corey Hopkins 5,  Srinivasa N Raja 2,  Yun Guan 8,  Xinzhong Dong 9 10
Affiliations

Affiliations

  • 1 The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  • 2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
  • 3 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
  • 4 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
  • 5 Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center, Nashville, TN 37232.
  • 6 The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
  • 7 St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105.
  • 8 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; xdong2@jhmi.edu yguan1@jhmi.edu.
  • 9 The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; xdong2@jhmi.edu yguan1@jhmi.edu.
  • 10 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
PMID: 28223516 DOI: 10.1073/pnas.1615255114
Abstract

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1 This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated CA2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.

Keywords

DRG neurons; GPCR; MrgprX1; pain; positive allosteric modulator.

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