title: Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs.
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.
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Vemuri B
authors.initials: VB
authors.lastname: Reddy
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Shuohao
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Azimi
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Sarina B
authors.initials: SB
authors.lastname: Elmariah
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Lerner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002403:Cathepsins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011537:Pruritus / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D044462:Receptors, Proteinase-Activated; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002403:Cathepsins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D044462:Receptors, Proteinase-Activated; C470192:Mrgprx1 protein, mouse; C028217:cathepsin S