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 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.
Highlights
Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch
MrgprC11 is activated by SLIGRL and SLIGKV, the tethered ligand peptides of respective mouse and human protease-activated receptor-2 (PAR2), while MRGPRX2 is activated by SLIGKV2,3,5,6
We asked whether cysteine proteases could cleave the extracellular N-terminal portion of MrgprC11
Summary
Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. Specific members of the family of Mas-related G-protein-coupled receptors (Mrgprs) are expressed by a subset of nociceptive fibres[1] These receptors have been shown to bind select pruritogens in the periphery and mediate non-histaminergic itch[2,3]. In transgenic mice in which a cluster of Mrgprs has been ablated, cutaneous exposure to these pruritogens evokes significantly less scratching compared with wild-type (WT) controls These findings underscore the importance of this family of receptors to peripheral detection of non-histaminergic itch stimuli and the subsequent activation of itch-specific neural pathways. While several exogenous compounds trigger Mrgpr activation, endogenous ligands or modulators of MrgprA3 and MrgprC11 receptors have yet to be identified Both serine and cysteine proteases have been implicated in triggering itch and inflammation in the skin. These findings highlight the possibility that cysteine proteases may exert effects on other ‘non-PAR’ GPCRs and further suggest that proteases are capable of modulating GPCRs by multiple mechanisms
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