{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe renin‐angiotensin system (RAS) is central to cardiovascular and electrolyte regulation, a notion reinforced by the discovery of alamandine—a novel heptapeptide generated via angiotensin-converting enzyme‐2 activity—in which the peptide milieu has spurred interest in related receptor families. Among the Mas-related G protein-coupled receptors (MRGPRs), MRGPRD has emerged as a candidate capable of responding to peptide ligands such as alamandine as well as angiotensin-derived metabolites. Structural similarities with receptors like Mas have prompted investigations into its capacity to mediate arachidonic acid release upon stimulation with Ang-(1-7) and other angiotensin peptides, thus situating MRGPRD within a broader context of peptide-mediated signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn sensory neurons, MRGPRD assumes a pivotal role in pruriception. In situ hybridization studies in human dorsal root ganglia have revealed that MRGPRD is co-expressed with the nociceptive ion channel TRPV1. Functional experiments in nonhuman primates further demonstrated that activation of MRGPRD by its ligand beta-alanine evokes the sensation of itch by preferentially exciting subsets of polymodal C-fiber nociceptors. These findings highlight the receptor as a key mediator of sensory signals, supporting distinct mechanisms of itch processing in primates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in sensory perception, MRGPRD is implicated in inflammatory signaling and oncogenic processes. In vitro studies using MRGPRD-expressing cell lines have shown that beta-alanine stimulation triggers the release of interleukin-6 via activation of a Gαq/phospholipase C pathway culminating in NF-κB activation, thereby linking MRGPRD to inflammatory responses. Moreover, overexpression of MRGPRD in fibroblastic cell models promotes hallmark features of transformation, including loss of contact inhibition, anchorage-independent growth, and in vivo tumor formation. Clinically, elevated expression levels of MRGPRD in renal carcinoma specimens are associated with aggressive tumor phenotypes and poorer patient survival, underscoring its potential as a prognostic biomarker and a novel target for anticancer therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Roberto Queiroga Lautner, Daniel C Villela, Rodrigo A Fraga-Silva, et al. 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"}, {"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": "Satoko Nishimura, Makiko Uno, Yasuyuki Kaneta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MRGD, a MAS-related G-protein coupled receptor, promotes tumorigenisis and is highly expressed in lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0038618"}], "href": "https://doi.org/10.1371/journal.pone.0038618"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22715397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22715397"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rohit Arora, Kenny M Van Theemsche, Samuel Van Remoortel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Constitutive, Basal, and β-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor D Induces Release of the Inflammatory Cytokine IL-6 and Is Dependent on NF-κB Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms222413254"}], "href": "https://doi.org/10.3390/ijms222413254"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34948051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34948051"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Gorka Larrinaga, Asier Valdivia, Inés Arrieta-Aguirre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms25031499"}], "href": "https://doi.org/10.3390/ijms25031499"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38338778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38338778"}]}]}]}