Structure, function and pharmacology of human itch GPCRs

Cao, Chuanai; Kang, Hye Jin; Singh, Isha; Chen, He; Zhang, Chengwei; Ye, Wenlei; Hayes, Byron W.; Liu, Jing; Gumpper, Ryan H.; Bender, Brian J.; Slocum, Samuel T.; Krumm, Brian E.; Lansu, Katherine; McCorvy, John D.; Kroeze, Wesley K.; English, Justin G.; DiBerto, Jeffrey F.; Huang, Xi‐Ping; Zhang, Shicheng; Liu, Yongfeng; Kim, Kuglae; Karpiak, Joel; Jan, Yuh Nung; Abraham, Soman N.; Jin, Jian; Shoichet, Brian K.; Fay, Jonathan F.; Roth, Bryan L.

doi:10.1038/s41586-021-04126-6

Cited by 110 publications

(109 citation statements)

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“…In mastoparan-activated HEK293-MRGPRX2 cells, however, only G αq activation was observed [52]. Using transducerome screening by a technique named Trupath, a recent study found that MRGPRX2 can couple to most of the 14 G α proteins at least under the conditions of overexpression in HEK293 transfectants [53]. The collective data hint at variability across cell types with non-MCs (such as MRGPRX2transfected HEK293) chiefly employing G αq (in the absence of G protein overexpression), while cells with MC characteristics (LAD2, RBL-MRGPRX2) showed coupling to both G αi and G αq .…”

Section: Discussionmentioning

confidence: 99%

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

Wang

Franke

Bal

et al. 2022

Cells

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The recent discovery of MRGPRX2 explains mast cell (MC)-dependent symptoms independently of FcεRI-activation. Because of its novelty, signaling cascades triggered by MRGPRX2 are rudimentarily understood, especially in cutaneous MCs, by which MRGPRX2 is chiefly expressed. Here, MCs purified from human skin were used following preculture or ex vivo and stimulated by FcεRI-aggregation or MRGPRX2 agonists (compound 48/80, Substance P) in the presence/absence of inhibitors. Degranulation was assessed by β-hexosaminidase or histamine release. Phosphorylation events were studied by immunoblotting. As a G protein-coupled receptor, MRGPRX2 signals by activating G proteins; however, their nature has remained controversial. In skin MCs, Gαi and Gαq were required for degranulation, but Gαi was clearly more relevant. Ca++ channels were likewise crucial. Downstream, PI3K was essential for granule discharge initiated by MRGPRX2 or FcεRI. ERK1/2 and JNK were additional participants, especially in the allergic route. Addressing possible points of intersection between early and later events, pERK1/2 and pAKT were found to depend on Gαi, further highlighting its significance. Gαq and Ca++ channels made some contributions to the phosphorylation of ERK. Ca++ differentially affected PI3K activation in FcεRI- vis-à-vis MRGPRX2-signaling, as channel inhibition increased pAKT only when triggered via FcεRI. Collectively, our study significantly extends our understanding of the molecular framework behind granule secretion from skin MCs.

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Section: Discussionmentioning

confidence: 99%

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

Wang

Franke

Bal

et al. 2022

Cells

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“…Yang et al 7 and Cao et al 8 have simultaneously solved the structure of agonist-stabilized MRGPRX2 by using cryogenic electron microscopy. Together, these studies shed critical light on how MRGPRX2 may recognize a breadth of structurally distinct cationic molecules.…”

Section: Nous) Factors Independently Of Ige (Fig 1)mentioning

confidence: 99%

“…Together, these studies shed critical light on how MRGPRX2 may recognize a breadth of structurally distinct cationic molecules. Yang et al 7 and Cao et al 8 noted that in contrast to the canonic family A GPCRs, MRGPRX2 has a shallow binding pocket with an acidic, negatively charged subpocket that facilitates MRGPRX2 binding by its cationic ligands. Additionally, there was notable heterogeneity in how different ligands bound, which may help explain the somewhat promiscuous binding of this receptor.…”

Section: Nous) Factors Independently Of Ige (Fig 1)mentioning

confidence: 99%

“…In further contrast to other GPRCRs, MRGPRX2 lacked the classic ''toggle switch,'' which initiates conformational changes necessary for receptor activation. Instead, Yang et al 7 and Cao et al 8 identified unique and uncommon structures critical for MRGPRX2 activation such as a ''kink'' in transmembrane domain 6 (TM6) that was conserved across the Mrgpr family. Through these insights into ligand binding, Yang et al identified a common peptide motif present in several peptidergic allergens that is necessary for MRGPRX2 recognition, which may aid in identifying new agonists.…”

Section: Nous) Factors Independently Of Ige (Fig 1)mentioning

confidence: 99%

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Structural insights into MRGPRX2: A new vision of itch and allergy

Trier

Kim

2022

Journal of Allergy and Clinical Immunology

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“…MRGPRX4, also known as sensory neuron-specific G-Protein coupled receptor 5/6, is involved in cholestatic itch [62,180,181]. DCA, CDCA, CA, and LCA evoke itching of human skin via the activation of MRGPRX4 expression in dorsal root ganglion (DRG) neurons [62].…”

Section: The Role Of Modified Bas In the Nervous Systemmentioning

confidence: 99%

Physiological Role of Bile Acids Modified by the Gut Microbiome

Kiriyama

Nochi

2021

Microorganisms

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Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems.

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Structure, function and pharmacology of human itch GPCRs

Cited by 110 publications

References 50 publications

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

Structural insights into MRGPRX2: A new vision of itch and allergy

Physiological Role of Bile Acids Modified by the Gut Microbiome

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