Structure, function and pharmacology of human itch receptor complexes

Yang, Fan; Guo, Lulu; Liu, Yü; Wang, Guopeng; Jia, Weiping; Zhang, Chao; Fang, Guoxing; Xu, Chen; Liu, Lei; Xu, Yan; Li, Qun; Qu, Changxiu; Xu, Yaping; Peng, Xiao; Zhu, Zhongliang; Li, Zijian; Zhou, Jiuyao; Yu, Xiao; Gao, Ning; Sun, Junying

doi:10.1038/s41586-021-04077-y

Cited by 80 publications

(76 citation statements)

References 45 publications

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“…As a G protein-coupled receptor (GPCR), MRGPRX2 initiates signaling by activation of G proteins. Which G protein subsets are involved is not completely clear, since pertussis toxin (PTX), a G αi inhibitor [10,11]), and YM-254890, that is G αq specific [12], have been variably shown to interfere with MRGPRX2 signaling [13][14][15]; it is assumed that the cell type expressing MRGPRX2 plays a decisive role, but no data are currently available for skin MCs. However, cutaneous MCs are not only the most abundant MC population in the body [16], but they also express the highest levels of MRGPRX2 and respond most vigorously to its ligands [17][18][19][20].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…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. 7 Cao et al also demonstrated how this new insight into the structure of MRPGRX2 can aid future efforts in drug development by identifying 2 potent MRGPRX2 antagonists that have a high level of specificity. 8 Together, these 2 studies illustrate how structure-function relationships can be exploited for future identification of novel therapies (Fig 1).…”

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

confidence: 97%

“…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%

See 2 more Smart Citations

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

Trier

Kim

2022

Journal of Allergy and Clinical Immunology

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β‐Phenethylamine Synthesis: N‐Pyridinium Aziridines as Latent Dual Electrophiles

Samanta,

Biswas,

O'Bannon

et al. 2024

Angewandte Chemie

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ß‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of ß‐phenethylamines. Bromide‐promoted ring opening generates ß‐halopyridinium amines. Selective Ni‐catalyzed C–C cross‐coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N–N bond activation within the b‐functionalized phenethylamino‐pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis

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Structure, function and pharmacology of human itch receptor complexes

Cited by 80 publications

References 45 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

β‐Phenethylamine Synthesis: N‐Pyridinium Aziridines as Latent Dual Electrophiles

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