The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia

Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Science Signaling (Impact Factor: 6.28). 07/2011; 4(181):ra45. DOI: 10.1126/scisignal.2001925
Source: PubMed


Itch has been defined as an unpleasant skin sensation that triggers the urge to scratch. Primary sensory dorsal root ganglia neurons detect itch stimuli through peripheral axons in the skin, playing an important role in generating itch. Itch is broadly categorized as histaminergic (sensitive to antihistamines) or nonhistaminergic. The peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) is an itch-inducing agent widely used to study histamine-independent itch. Here, we show that Mrgprs (Mas-related G protein-coupled receptors), particularly MrgprC11, rather than PAR2 (protease-activated receptor 2) as previously thought, mediate this type of itch. A shorter peptide, SLIGR, which specifically activates PAR2 but not MrgprC11, induced thermal pain hypersensitivity in mice but not a scratch response. Therefore, although both Mrgpr and PAR2 are SLIGRL-responsive G protein-coupled receptors present in dorsal root ganglia, each plays a specific role in mediating itch and pain.

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    • "Although it is generally accepted that this type of itch is mediated by PAR2, no study has directly addressed this issue (e.g., using PAR2-knockout mice). Because SLIGRL is used widely as a pruritogen for studying histamineindependent itch, we tested the ability of this peptide to induce itch in Mrgprcluster Δ À/À mice (Liu et al. 2011). To our surprise, the Mrgpr-cluster Δ À/À mice scratched significantly less in response to SLIGRL injection compared with their wild-type littermates. "
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    ABSTRACT: Itch is a complex sensory modality that can be evoked by an extremely diverse set of stimuli and has multiple components of disease etiology. Thus, determining the basic molecular and cellular players is essential before we can tackle the more complex aspects of itch. The identification of novel itch receptors has been extremely fruitful and has uncovered novel signaling pathways and pruritogens. Mrgprs encode a family of G protein-coupled receptors, many of which are expressed specifically in sensory nerves and function as itch receptors in mediating histamine-independent itch. In this chapter, we will review the discovery of the receptor family, their specific expression, their roles as itch receptors, and the itch-inducing agonists. Furthermore, we will summarize the results indicating that Mrgpr-expressing sensory neurons are itch-sensing neurons. In the end we will discuss the role of Mrgprs and Mrgpr-positive neurons in chronic itch.
    No preview · Article · Apr 2015 · Handbook of experimental pharmacology
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    • "Another functionally important ligand of mMrgprX1 is the peptide SLIGRL, which is released from the protease activated receptor 2 upon trypsin digestion (Liu et al., 2011), and which is responsible for the itch response induced by intradermal trypsin injections. He et al. (2014) recently showed that the hMRGPRX1 antagonist, 2,3-disubstituted azabicyclo-octane (Kunapuli et al., 2006), also blocks rMrgprX1 and mMrgprX1. "
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    ABSTRACT: The Mas-related G protein-coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as β-alanine, alamandine, adenine, RF-amide peptides, or salusin-β. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1-7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
    Full-text · Article · Oct 2014 · Pharmacological reviews
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    • "We caution against attributing much significance to this observation, as it may reflect a pharmacologic rather than a physiologic phenomenon. For comparison, in studies of scratching in mice, SLIGRL is used as a positive control in mM concentrations[37]. "
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    ABSTRACT: Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation.
    Full-text · Article · Jun 2014 · PLoS ONE
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