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Although histamine is an important physiologically active substance in pruritus,antihistamine drugs can only relieve a small proportion of symptoms in chronic pruritus. A wealth of pharmacological, clinical, electrophysiological and molecular databases supports the existence of the histamine-independent pruritus. Here, we review the progress of research on Mas-related G protein-coupled receptors (Mrgprs), related ligands, and their interactions. Mrgprs are mainly expressed in small-diameter dorsal root ganglion nerve cells and are involved in the pruritic process, and their family members are associated with the production of itch and nociception. All these findings point to a new direction for the treatment of pruritus.

Mas-related G protein-coupled receptors (MRGPRs) primarily function as itch and pain receptors and display diverse downstream signaling pathways. MRGPRs are fast-evolving proteins with highly diverse amino acid sequences across different species and display high allele frequencies of the missense mutations in humans. MRGPRs have shallow ligand-binding pockets with distinct residue composition, pocket size, and charge distribution for the recognition of structurally distinct endogenous or exogenous agonists. Technical advances in G protein-coupled receptor (GPCR) inactive structure determination may facilitate the pursuing of inactive MRGPR structures, which could be used as important templates for structure-based drug discovery of novel MRGPR antagonists. Mas-related G protein-coupled receptor (MRGPR) family members play important roles in the sensation of noxious stimuli and represent novel targets for the treatment of itch and pain. MRGPRs recognize a diversity of agonists and display complicated downstream signaling profiles, high sequence diversity across species, and many polymorphisms in humans. The recent structural advances on MRGPRs reveal unique structural features and diverse agonist recognition modes of this receptor family, which should facilitate the structure-based drug discovery at MRGPRs. In addition, the newly discovered ligands also provide valuable tools to explore the function and the therapeutic potential of MRGPRs. In this review, we discuss these progresses in our understanding of MRGPRs and highlight the challenges and potential opportunities for the future drug discovery at these receptors. [ABSTRACT FROM AUTHOR]

Abstract: Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca 2+ -activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca 2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1 -deficient mice rescued the impaired itching observed in Ano1 -deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes. [ABSTRACT FROM AUTHOR]

Itch is an uncomfortable feeling that evokes a desire to scratch. This protective reflex can effectively eliminate parasites that invade the skin. When itchy skin becomes severe or lasts for more than six weeks, it has deleterious effects on both quality of life and productivity. Despite decades of research, the complete molecular and cellular coding of chronic itch remains elusive. This persistent condition often defies treatment, including with antihistamines, and poses a significant societal challenge. Obtaining pathophysiological insights into the generation of chronic itch is essential for understanding its mechanisms and the development of innovative anti-itch medications. In this review we provide a systematic overview of the recent advancement in itch research, alongside the progress made in drug discovery within this field. We have examined the diversity and complexity of the classification and mechanisms underlying the complex sensation of itch. We have also delved into recent advancements in the field of itch mechanism research and how these findings hold potential for the development of new itch treatment medications. But the treatment of clinical itch symptoms still faces significant challenges. Future research needs to continue to delve deeper, not only to discover more itch-related pathways but also to explore how to improve treatment efficacy through multitarget or combination therapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Although the Mas‐related G‐protein–coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD)–associated itch remains unclear. Objectives: To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets. Methods: Mrgpr‐clusterΔ–/– mice and human MrgprX1 (hMrgprX1) transgenic mice were used to evaluate the function of Mrgprs in oxazolone‐induced ACD. Results: Utilizing an ACD model, we found that Mrgpr‐clusterΔ–/– mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr‐clusterΔ–/– mice, the expression of MrgprC11 and MrgprA3 was significantly increased in the ACD model, which also innervated the skin and spinal cord at higher‐than‐normal densities. The proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8‐22 and chloroquine were also remarkably increased in the ACD model, resulting in enhanced itch behaviour. To study the function of human Mrgprs in ACD‐induced itch, we used hMrgprX1 transgenic mice, which rescued the severe itch defect of Mrgpr‐clusterΔ–/– mice in the ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse. Conclusions: Our study provides the first evidence that Mrgprs are involved in ACD‐induced chronic itch, which provides new avenues for itch management in ACD. [ABSTRACT FROM AUTHOR]

Itch arising from glabrous skin (palms and soles) has attracted limited attention within the field due to the lack of methodology. This is despite glabrous itch arising from many medical conditions such as plantar and palmar psoriasis, dyshidrosis, and cholestasis. Therefore, we developed a mouse glabrous skin behavioral assay to investigate the contribution of three previously identified pruriceptive neurons in glabrous skin itch. Our results show that MrgprA3+ and MrgprD+ neurons, although key mediators for hairy skin itch, do not play important roles in glabrous skin itch, demonstrating a mechanistic difference in itch sensation between hairy and glabrous skin. We found that MrgprC11+ neurons are the major mediators for glabrous skin itch. Activation of MrgprC11+ neurons induced glabrous skin itch, while ablation of MrgprC11+ neurons reduced both acute and chronic glabrous skin itch. Our study provides insights into the mechanisms of itch and opens up new avenues for future glabrous skin itch research. [ABSTRACT FROM AUTHOR]

The discovery of Mas-related G protein-coupled receptors (MRGPRs) in itch sensation promised a search for novel therapeutics of itch that ultimately met with little success. Recent structural determination of these receptors by Roth and Sun marks a big step forward in the search for therapeutics of debilitating itch. [ABSTRACT FROM AUTHOR]

MRGPRs(Mas related G protein coupled receptors) is a new G protein family found in recent years and they selectively high express in primary sensory neurons of dorsal root(DRG) and trigeminal ganglia(TG),as well as mast cells, indicating these receptors play important roles in the modulation of somatosensory functions. Knowledge of MRGPRs have made us further understand the nociception pathways and thus will help us to develop new analgesic drugs with less side effects.This review article summarizes the findings published in recent years on the ligand, signaling and physiology of hMRGPRs family. [ABSTRACT FROM AUTHOR]

Tick bites severely threaten human health because they allow the transmission of many deadly pathogens, including viruses, bacteria, protozoa, and helminths. Pruritus is a leading symptom of tick bites, but its molecular and neural bases remain elusive. This study sought to discover potent drugs and targets for the specific prevention and treatment of tick bite–induced pruritus and arthropod-related itch. We used live-cell calcium imaging, patch-clamp recordings, and genetic ablation and evaluated mouse behavior to investigate the molecular and neural bases of tick bite–induced pruritus. We found that 2 tick salivary peptides, IP defensin 1 (IPDef1) and IR defensin 2 (IRDef2), induced itch in mice. IPDef1 was further revealed to have a stronger pruritogenic potential than IRDef2 and to induce pruritus in a histamine-independent manner. IPDef1 evoked itch by activating mouse MrgprC11 and human MRGPRX1 on dorsal root ganglion neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on dorsal root ganglion neurons. Moreover, IPDef1 also activated mouse MrgprB2 and its ortholog human MRGPRX2 selectively expressed on mast cells, inducing the release of inflammatory cytokines and driving acute inflammation in mice, although mast cell activation did not contribute to oxidated IPDef1–induced itch. Our study identifies tick salivary peptides as a new class of pruritogens that initiate itch through MrgprC11/X1-TRPV1 signaling in pruritoceptors. Our work will provide potential drug targets for the prevention and treatment of pruritus induced by the bites or stings of tick and maybe other arthropods. [Display omitted] [ABSTRACT FROM AUTHOR]

• Mrgprs play critical roles in somatosensation at the neuroimmune interface. • Identification of specific Mrgprs on neurons innervating visceral organs reveal new functions. • Heterogeneity in Mrgpr regulation of mast cells and neurons reveals new neuroimmune physiology. Mas-related G coupled receptors (Mrgprs) are a superfamily of receptors expressed in sensory neurons that are known to transmit somatic sensations from the skin to the central nervous system. Interestingly, Mrgprs have recently been implicated in sensory and motor functions of mucosal-associated neuronal circuits. The gastrointestinal and pulmonary tracts are constantly exposed to noxious stimuli. Therefore, it is likely that neuronal Mrgpr signaling pathways in mucosal tissues, akin to their family members expressed in the skin, might relay messages that alert the host when mucosal tissues are affected by damaging signals. Further, Mrgprs have been proposed to mediate the cross-talk between sensory neurons and immune cells that promotes host-protective functions at barrier sites. Although the mechanisms by which Mrgprs are activated in mucosal tissues are not completely understood, these exciting studies implicate Mrgprs as potential therapeutic targets for conditions affecting the intestinal and airway mucosa. This review will highlight the central role of Mrgpr signaling pathways in the regulation of homeostasis at mucosal tissues. [ABSTRACT FROM AUTHOR]

• Mrgprs utilize canonical G protein signaling pathways. • Mrgprs couple to ion channels to excite neurons. • Functional implications of Mrgprs polymorphisms. Mas-related G protein-coupled receptors (Mrgprs) are a family of receptors implicated in a diverse array of human diseases. Since their discovery in 2001, great progress has been made in determining their relation to human disease. Vital for Mrgprs therapeutic efforts across all disease disciplines is a thorough understanding of Mrgprs signal transduction pathways and polymorphisms, as these offer insights into new drug candidates, existing discrepancies in drug response, and differences in disease susceptibility. In this review, we discuss the current state of knowledge regarding Mrgprs signaling pathways and polymorphisms. [ABSTRACT FROM AUTHOR]

Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration, QSMs induce transcriptional alterations in bacteria, which enable virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs, including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2, triggering mast cell degranulation, which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells, while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2 -knockout mice exhibit reduced bacterial clearance, while pharmacologically activating Mrgprb2 in vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an "Achilles heel" and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections. • The mammalian receptor Mrgprb2 and MRGPRX2 can detect bacterial QSMs • QSM detection by Mrgprb2 and MRGPRX2 in mast cells elicits antibacterial mediator release • Mrgprb2 recognition of QSMs is critical for an effective immune response to bacteria • Pharmacologic activation of Mrgprb2 and MRGPRX2 enhances bacterial clearance Bacteria use quorum-sensing signaling for cross-species communication. Pundir et al. report that host mast cells detect Gram-positive-bacteria-derived quorum-sensing molecules via the Mrgpr receptors. Mrgpr activation triggers antibacterial activity and immune cell recruitment to efficiently clear bacteria, while animals deficient in Mrgpr are hypersusceptible to bacterial infection. [ABSTRACT FROM AUTHOR]