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

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 recepto...

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Bibliographic Details
Published in:Nature communications 2015-07, Vol.6 (1), p.7864-7864, Article 7864
Main Authors: Reddy, Vemuri B., Sun, Shuohao, Azimi, Ehsan, Elmariah, Sarina B., Dong, Xinzhong, Lerner, Ethan A.
Format: Article
Language:English
Subjects:
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13/89
14/34
14/63
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631/45/612/194
631/80/86
64/60
692/1807/4018
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Animals
Blotting, Western
Cathepsins - metabolism
HeLa Cells
Humanities and Social Sciences
Humans
Mice
multidisciplinary
Pruritus - metabolism
Real-Time Polymerase Chain Reaction
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Receptors, Proteinase-Activated
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
Science
Science (multidisciplinary)
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Summary: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. Sensory neurons that mediate histamine-independent itch express Mas-related G protein coupled receptors (Mrgprs). Here, Reddy et al. show that the cysteine protease cathepsin S cleaves and activates MrgpcrC11 without the generation of a tethered ligand, in contrast to other protease activated receptors.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms8864