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更新于：2025-01-23

MRGPRX1

更新于：2025-01-23

基本信息

别名

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

+ [5]

简介

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.

关联

项与 MRGPRX1 相关的药物

ML382

靶点

MRGPRX1

作用机制

MRGPRX1 agonists

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

MRGPRX1 antagonists(Escient Pharmaceuticals)

靶点

MRGPRX1

作用机制

MRGPRX1拮抗剂

在研机构

Escient Pharmaceuticals, Inc.初创企业

原研机构

Escient Pharmaceuticals, Inc.初创企业

在研适应症-

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MRGPRX1 相关的临床结果

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100 项与 MRGPRX1 相关的转化医学

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0 项与 MRGPRX1 相关的专利（医药）

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项与 MRGPRX1 相关的文献（医药）

2024-12-01·Journal of Biological Chemistry

Evolutionary Scenarios for the Specific Recognition of Non-homologous Endogenous Peptides by G Protein-Coupled Receptor Paralogs

Article

作者: 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, MRGPRX 1, a paralog of MRGPRX2, recognizes BAM8-22, 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 (IDL) score" system, which estimates the amino acid residues responsible for peptide-GPCR interactions predicted by peptide descriptor (PD)-incorporated SVM, our original machine learning-based peptide-GPCR interaction predictor. An IDL 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 due to 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.

2024-11-01·Pain

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

Article

作者: 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.

2024-08-01·Environment International

Common genetic variants associated with urinary phthalate levels in children: A genome-wide study

Article

作者: Ruiz-Arenas, Carlos ; Wright, John ; Gützkow, Kristine B ; Casas, Maribel ; Andrusaityte, Sandra ; Chatzi, Leda ; Philippat, Claire ; Sakhi, Amrit Kaur ; Escaramís, Geòrgia ; Thomsen, Cathrine ; Brantsæter, Anne-Lise ; Maitre, Lea ; Heude, Barbara ; Hough, Amy ; Yang, Tiffany C ; Buko, Zsanett ; Nurtdinov, Ramil N ; González, Juan R ; Grazuleviciene, Regina ; Bustamante, Mariona ; Vrijheid, Martine ; Vafeiadi, Marina ; Balagué-Dobón, Laura

INTRODUCTIONPhthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes.OBJECTIVEIn this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS).METHODSThe study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool.RESULTSWe identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion.CONCLUSIONThrough genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.

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