Substance P plays critical roles in itch and neurogenic inflammation. This neuropeptide has been thought to mediate its actions via the NK1 receptor. Unexpectedly, we have found that substance P is a potent agonist of human MrgX2 and mouse MrgA1, homologous members of the Mrgpr family of receptors that been linked strongly to itch and nociception. SP-evoked scratching is reduced to baseline in Mrg knockout mice. We hypothesize that human MrgprX2 and mouse MrgprA1 play critical roles in SP-induced itch. Evaluating this hypothesis has the potential to be transformative by providing new insights into understanding the basic mechanisms of itch while identifying therapeutic targets leading to new medications for those who suffer from itch.

Public Health Relevance

Substance P is a peptide associated with itch and inflammation. We have identified a new way by which this peptide works. These findings have the potential to lead to new drugs to treat itch and inflammation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Tseng, Hung H
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Massachusetts General Hospital
United States
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Reddy, Vemuri B; Azimi, Ehsan; Chu, Lei et al. (2018) Mas-Related G-Protein Coupled Receptors and Cowhage-Induced Itch. J Invest Dermatol 138:461-464
Lerner, Ethan A (2018) Pathophysiology of Itch. Dermatol Clin 36:175-177
Pereira, Paula J S; Lerner, Ethan A (2017) Gate Control Theory Springs a Leak. Neuron 93:723-724
Haddadi, Nazgol-Sadat; Foroutan, Arash; Ostadhadi, Sattar et al. (2017) Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice. Acta Derm Venereol 97:571-577
Reddy, Vemuri B; Graham, Thomas A; Azimi, Ehsan et al. (2017) A single amino acid in MRGPRX2 necessary for binding and activation by pruritogens. J Allergy Clin Immunol 140:1726-1728
Azimi, Ehsan; Reddy, Vemuri B; Lerner, Ethan A (2017) Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2:
Reddy, Vemuri B; Lerner, Ethan A (2017) Activation of mas-related G-protein-coupled receptors by the house dust mite cysteine protease Der p1 provides a new mechanism linking allergy and inflammation. J Biol Chem 292:17399-17406
Azimi, Ehsan; Reddy, Vemuri B; Pereira, Paula Juliana Seadi et al. (2017) Substance P activates Mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol 140:447-453.e3
Azimi, Ehsan; Lerner, Ethan A (2017) Implications of MRGPRX2 in human and experimental cardiometabolic diseases. Nat Rev Cardiol 14:124
Azimi, Ehsan; Reddy, Vemuri B; Shade, Kai-Ting C et al. (2016) Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 1:e89362

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