Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs

Vemuri B. Reddy, Shuohao Sun, Ehsan Azimi, Sarina B. Elmariah, Xinzhong Dong and Ethan A. Lerner ()
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Vemuri B. Reddy: Cutaneous Biology Research Center, Massachusetts General Hospital
Shuohao Sun: Johns Hopkins University
Ehsan Azimi: Cutaneous Biology Research Center, Massachusetts General Hospital
Sarina B. Elmariah: Cutaneous Biology Research Center, Massachusetts General Hospital
Xinzhong Dong: Johns Hopkins University
Ethan A. Lerner: Cutaneous Biology Research Center, Massachusetts General Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. We show that the cysteine protease cathepsin S activates MrgprC11 and evokes receptor-dependent scratching in mice. In contrast to its activation of conventional protease-activated receptors, cathepsin S-mediated activation of MrgprC11 did not involve the generation of a tethered ligand. We demonstrate further that different cysteine proteases selectively activate specific mouse and human Mrgpr family members. This expansion of our understanding by which proteases interact with G-protein-coupled receptors (GPCRs) redefines the concept of what constitutes a protease-activated receptor. The findings also implicate proteases as ligands to members of this orphan receptor family while providing new insights into how cysteine proteases contribute to itch.

Date: 2015
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DOI: 10.1038/ncomms8864

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