PowerPoint Presentation
Role of MRGPRs in substance P signaling, itch, and mast cell activation
Authors
Yanek Jiménez-Andrade, Lilah Gmyrek, Jamie Harden, Jeegar Patel, Hans Hofland, Jin Mo Park, and Ethan A. Lerner
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Evommune, Palo Alto, California, USA
Presenting author (Email, yjimenezandrade@mgh.harvard.edu)
Introduction
Mas-related G-protein coupled receptor (MRGPR) family proteins function as innate sensors for pruritogens and play a crucial role in itch and neurogenic inflammation. Our previous studies demonstrated that the neuropeptide substance P (SP) exerted its physiologic function via MRGPRs, in addition to its conventional receptor, the neurokinin-1 receptor.
Aim
We sought to determine the role of MrgprA1 and MrgprB2, two mouse proteins homologous to MRGPRX2 in humans, in SP-induced itch and mast cell activation.
Material and Methods
Generation of MrgprA1 knock out (A1-KO) mice
Generation of MrgprB2 knock out (B2-KO) mice
| Ligand | WT-DRG neurons | A1-KO DRG neurons |
|---|---|---|
| Substance P (1μM) | + | - |
| Chloroquine (1mM) | $^{+}$ | + |
Substance P stimulates dorsal root ganglion (DRGs) WT but not A1-KO neurons.
Substance P evokes scratching behavior in WT mice, and A1-KO mice show a reduced response.
Conclusions
Figure 1. Scratching behavior was evaluated in A1-WT and A1-KO mice. Mouse experiment workflow: Mice received an intradermal injection of 10 μL containing Substance P (500 μmol/L) into the right cheek, delivered by a 31-G needle. The injection site is shown in the red circle (A). Time course of the effect of substance P on scratching behavior over 30 (B). The cumulative number of scratching bouts observed for 30 minutes (C). Results are means ± SEM (n=12-15 mice/group) combined from three independent experiments.
Acknowledgments
This study was supported by the National Eczema Association, grant NEA20-ECRG137 and a fund under a sponsored research agreement with Evommune.
References
- Akiyama, T., et al., Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain, 2014. 155(1): p. 80-92.
- Mollanazar, N.K., P.K. Smith, and G. Yosipovitch, Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clin Rev Allergy Immunol, 2016. 51(3): p. 263-292.
- Kuhn, H., et al., Mas-related G protein-coupled receptor X2 and its activators in dermatologic allergies. J Allergy Clin Immunol, 2020.
- Azimi, E., et al., Substance P activates Mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol, 2017. 140(2): p. 447-453 e3.
- Azimi, E., et al., Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight, 2016. 1(16): p. e89362.
- Liu, Q., et al., Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell, 2009. 139(7): p. 1353-65.
This knowledge supports the development of MRGPR inhibitors for the treatment of itch, dermatitis, and other MRGPR-driven pathologic conditions.