{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman Mas‑related G protein‑coupled receptor X1 (MRGPRX1) is a primate‑specific receptor with a highly restricted expression in primary sensory neurons, where it plays a key role in mediating both pain and itch. Functional studies using innovative humanized mouse models have demonstrated that MRGPRX1 activation by ligands such as BAM8‑22 or via a positive allosteric modulator leads to inhibition of high‑voltage‑activated Ca²⁺ channels and attenuation of spinal nociceptive transmission, thereby providing effective pain relief. These findings highlight the promise of targeting MRGPRX1 for therapeutic pain inhibition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have revealed that MRGPRX1 is activated not only by BAM8‑22 but also by pruritogens such as the cysteine protease mucunain—an active component of cowhage—that together initiate itch via calcium‐dependent signaling in dorsal root ganglion neurons. This ligand‐induced activation emphasizes the receptor’s dual role in both nociceptive and pruritoceptive pathways, establishing MRGPRX1 as a critical mediator of sensory perception."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent cryo‑electron microscopy studies have provided structural insights into MRGPRX1 that clarify its mechanism of activation and downstream signaling. One investigation unraveled the structure of the receptor bound to a potent synthetic agonist (compound 16), revealing a shallow orthosteric pocket that underlies its selective ligand recognition. In a complementary study, cryo‑EM structures of MRGPRX1 coupled to both Gi and Gq proteins in complex with peptides (BAM8‑22 and CNF‑Tx2) identified unique features—such as the distinct accommodation of a C‑terminal “RF/RY” motif and a critical transmembrane motif that drives receptor activation—that are essential for its dual G‑protein coupling. Together, these structural observations lay the groundwork for developing specific modulators aimed at alleviating itch and pain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hans Jürgen Solinski, Susanna Zierler, Thomas Gudermann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human sensory neuron-specific Mas-related G protein-coupled receptors-X1 sensitize and directly activate transient receptor potential cation channel V1 via distinct signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.408617"}], "href": "https://doi.org/10.1074/jbc.M112.408617"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23074220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23074220"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhe Li, Pang-Yen Tseng, Vinod Tiwari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1615255114"}], "href": "https://doi.org/10.1073/pnas.1615255114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28223516"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28223516"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Amanda Klein, Hans Jürgen Solinski, Nathalie M Malewicz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.64506"}], "href": "https://doi.org/10.7554/eLife.64506"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33891544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33891544"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bing Gan, Leiye Yu, Haifeng Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of agonist-induced activation of the human itch receptor MRGPRX1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.3001975"}], "href": "https://doi.org/10.1371/journal.pbio.3001975"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37347749"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37347749"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lulu Guo, Yumu Zhang, Guoxing Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ligand recognition and G protein coupling of the human itch receptor MRGPRX1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-023-40705-z"}], "href": "https://doi.org/10.1038/s41467-023-40705-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37591889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37591889"}]}]}]}