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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    • "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.
    Pharmacological reviews 10/2014; 66(4):1080-1105. DOI:10.1124/pr.113.008136 · 17.10 Impact Factor
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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.
    PLoS ONE 06/2014; 9(6):e99702. DOI:10.1371/journal.pone.0099702 · 3.23 Impact Factor
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    • "It has been demonstrated that MrgprC11 can be activated by the PAR2 peptide agonist SLIGRL-NH2, (EC50 = 10 µM) however, the Leu6-truncated peptide, SLIGR-NH2, lost MrgprC11 signaling capacity while retaining PAR2 activity [12]. To examine PAR2/MrgprC11 selectivity, we evaluated Ca2+ responses in MrgprC11 transfected CHO cells [12] with the parent peptidomimetic, 2at-LIGR-NH2 and the most potent STL compounds (1, 2) from this study (Figure 8). "
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    ABSTRACT: Protease-activated receptor-2 (PAR2) is a G-Protein Coupled Receptor (GPCR) activated by proteolytic cleavage to expose an attached, tethered ligand (SLIGRL). We evaluated the ability for lipid-tethered-peptidomimetics to activate PAR2 with in vitro physiological and Ca2+ signaling assays to determine minimal components necessary for potent, specific and full PAR2 activation. A known PAR2 activating compound containing a hexadecyl (Hdc) lipid via three polyethylene glycol (PEG) linkers (2at-LIGRL-PEG3-Hdc) provided a potent agonist starting point (physiological EC50 = 1.4 nM; 95% CI: 1.2–2.3 nM). In a set of truncated analogs, 2at-LIGR-PEG3-Hdc retained potency (EC50 = 2.1 nM; 1.3–3.4 nM) with improved selectivity for PAR2 over Mas1 related G-protein coupled receptor type C11, a GPCR that can be activated by the PAR2 peptide agonist, SLIGRL-NH2. 2at-LIG-PEG3-Hdc was the smallest full PAR2 agonist, albeit with a reduced EC50 (46 nM; 20–100 nM). 2at-LI-PEG3-Hdc retained specific activity for PAR2 with reduced EC50 (310 nM; 260–360 nM) but displayed partial PAR2 activation in both physiological and Ca2+ signaling assays. Further truncation (2at-L-PEG3-Hdc and 2at-PEG3-Hdc) eliminated in vitro activity. When used in vivo, full and partial PAR2 in vitro agonists evoked mechanical hypersensitivity at a 15 pmole dose while 2at-L-PEG3-Hdc lacked efficacy. Minimum peptidomimetic PAR2 agonists were developed with known heterocycle substitutes for Ser1 (isoxazole or aminothiazoyl) and cyclohexylalanine (Cha) as a substitute for Leu2. Both heterocycle-tetrapeptide and heterocycle-dipeptides displayed PAR2 specificity, however, only the heterocycle-tetrapeptides displayed full PAR2 agonism. Using the lipid-tethered-peptidomimetic approach we have developed novel structure activity relationships for PAR2 that allows for selective probing of PAR2 function across a broad range of physiological systems.
    PLoS ONE 06/2014; 9(6):e99140. DOI:10.1371/journal.pone.0099140 · 3.23 Impact Factor
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