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Last update 08 May 2025

MRGPRX1

Last update 08 May 2025

Basic Info

Synonyms

MAS related GPR family member X1, Mas-related G-protein coupled receptor member X1, MAS-related GPR, member X1

+ [5]

Introduction

Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain. Potently activated by enkephalins including BAM22 (bovine adrenal medulla peptide 22) and BAM (8-22) (PubMed:26582731). BAM22 is the most potent compound and evoked a large and dose-dependent release of intracellular calcium in stably transfected cells. G(alpha)q proteins are involved in the calcium-signaling pathway. Activated by the antimalarial drug, chloroquine. May mediate chloroquine-induced itch, in a histamine-independent manner.

Drugs associated with MRGPRX1

MRGPRX1 antagonists(Escient Pharmaceuticals)

Target

MRGPRX1

Mechanism

MRGPRX1 antagonists

Active Org.

Escient Pharmaceuticals, Inc.

Originator Org.

Escient Pharmaceuticals, Inc.

Active Indication-

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

US20240002395

Patent Mining

Target

MRGPRX1

Mechanism-

Active Org.

The Johns Hopkins University

Originator Org.

The Johns Hopkins University

Active Indication

Nervous System Diseases [+2]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ML382

Target

MRGPRX1

Mechanism

MRGPRX1 agonists

Active Org.-

Originator Org.

Vanderbilt University

Active Indication-

Inactive Indication-

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MRGPRX1

100 Translational Medicine associated with MRGPRX1

0 Patents (Medical) associated with MRGPRX1

Literatures (Medical) associated with MRGPRX1

01 Mar 2025·Journal of Investigative Dermatology

The Fungal Secretory Peptide Micasin Induces Itch by Activating MRGPRX1/C11/A1 on Peripheral Neurons

Article

Author: Yu, Leiye ; Gan, Bing ; Kwok, Hang Fai ; Wu, Yingliang ; Cao, Zhijian ; Yang, Haifeng ; Ren, Ruobing ; Chen, Yian ; Wang, Luyao

Pruritus is the leading symptom of dermatophytosis. Microsporium canis is one of the predominant dermatophytes causing dermatophytosis. However, the pruritogenic agents and the related molecular mechanisms of the dermatophyte M canis remain poorly understood. In this study, the secretion of the dermatophyte M canis was found to dose-dependently evoke itch in mice. The fungal peptide micasin secreted from M canis was then identified to elicit mouse significant scratching and itching responses. The peptide micasin was further revealed to directly activate mouse dorsal root ganglia neurons to mediate the nonhistaminergic itch. Knockout and antagonistic experiments demonstrated that MRGPRX1/C11/A1 rather than MRGPRX2/b2 activated by micasin contributed to pruritus. The chimeras and single-amino acid variants of MRGPRX1 showed that 3 domains (extracellular loop 3, transmembrane helical domain 3, and transmembrane helical domain 6) and 4 hydrophobic residues (Y99, F237, L240, and W241) of MRGPRX1 played the key role in micasin-triggered MRGPRX1 activation. Our study sheds light on the dermatophytosis-associated pruritus and may provide potential therapeutic targets and strategies against pruritus caused by dermatophytes.

01 Feb 2025·Journal of Biological Chemistry

Evolutionary scenarios for the specific recognition of nonhomologous endogenous peptides by G protein–coupled receptor paralogs

Article

Author: Shiraishi, Akira ; Satake, Honoo ; Wada, Azumi

Several peptides interact with phylogenetically unrelated G protein-coupled receptors (GPCRs); similarly, orthologous GPCRs interact with distinct ligands. The neuropeptide substance P (SP) activates both NK1R and another unrelated primate-specific GPCR, MRGPRX2. Furthermore, MRGPRX1, a paralog of MRGPRX2, recognizes BAM8-22 (bovine adrenal medulla peptide 8-22), which has no evolutionary relatedness to SP. To elucidate the molecular basis and evolutionary history of this phylogenetically unrelated ligand selectivity, we developed a systematic procedure, the "interaction determinant likelihood score" system, which estimates the amino acid residues responsible for peptide-GPCR interactions predicted by peptide descriptor-incorporated support vector machine, our original machine learning-based peptide-GPCR interaction predictor. An interaction determinant likelihood score-based approach followed by pharmacological validation revealed the determinant residues for the ligand selectivity of SP-MRGPRX2 (F3.24 and G4.61) and BAM8-22-MRGPRX1 (L1.35). Molecular phylogenetic analysis revealed that the MRGPRX1 of common ancestral primates recognized BAM8-22, whereas the ancestral Cercopithecinae MRGPRX1 lost its interaction with BAM8-22 because of the loss of L1.35. The SP-MRGPRX2 interaction emerged in the common ancestors of Euarchonta, and, thereafter, the interaction of MRGPRX2 with both SP and BAM8-22 was acquired via substitution with L1.35 in several lineages. Collectively, the present study unraveled the molecular mechanisms and evolution of ligand specificity in evolutionary unrelated GPCRs.

01 Nov 2024·Pain

RNA isoform expression landscape of the human dorsal root ganglion generated from long-read sequencing

Article

Author: Mwirigi, Juliet M ; Price, Theodore J ; Arendt-Tranholm, Asta

AbstractSplicing is a posttranscriptional RNA processing mechanism that enhances genomic complexity by creating multiple isoforms from the same gene. We aimed to characterize the isoforms expressed in the human peripheral nervous system, with the goal of creating a resource to identify novel isoforms of functionally relevant genes associated with somatosensation and nociception. We used long-read sequencing to document isoform expression in the human dorsal root ganglia from 3 organ donors and validated in silico by confirming expression in short-read sequencing from 3 independent organ donors. Nineteen thousand five hundred forty-seven isoforms of protein-coding genes were detected and validated. We identified 763 isoforms with at least one previously undescribed splice junction. Previously unannotated isoforms of multiple pain-associated genes, including ASIC3, MRGPRX1, and HNRNPK, were identified. In the novel isoforms of ASIC3, a region comprising approximately 35% of the 5'UTR was excised. By contrast, a novel splice junction was used in isoforms of MRGPRX1 to include an additional exon upstream of the start codon, consequently adding a region to the 5'UTR. Novel isoforms of HNRNPK were identified, which used previously unannotated splice sites to both excise exon 14 and include a sequence in the 3' end of exon 13. This novel insertion is predicted to introduce a tyrosine phosphorylation site potentially phosphorylated by SRC. We also independently confirm a recently reported DRG-specific splicing event in WNK1 that gives insight into how painless peripheral neuropathy occurs when this gene is mutated. Our findings give a clear overview of mRNA isoform diversity in the human dorsal root ganglia obtained using long-read sequencing.

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MRGPRX1

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