Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

Occhiuto, Christopher J.; Kammala, Ananth Kumar; Yang, Canchai; Nellutla, Rithvik; Garcia, Marco; Gomez, Gregorio; Subramanian, Hariharan

doi:10.3389/fimmu.2019.03143

Cited by 34 publications

(18 citation statements)

References 69 publications

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“…Ligand stimulation of MRGPRX2 induces exocytosis via the phospholipase Cβ/calcineurin pathway after intracellular Ca 2+ mobilization in MCs [ 14 , 42 ]. Store-operated Ca 2+ entry via stromal interaction molecule 1 could promote MRGPRX2-induced human MC response and Mrgprb2-dependent inflammation in a mouse model [ 43 ], supporting that the Ca 2+ mobilizing mechanism is an important signal for the physiological function of MRGPRX2. It is also known that phosphatidylinositol 3-kinase (PI3K)/AKT, MAPKs such as c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (Erk1/2), p38), and nuclear factor-κB (NF-κB) are involved in cytokine production from MCs during allergy [ 44 , 45 , 46 , 47 ].…”

Section: Mrgprx2mentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

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Section: Mrgprx2mentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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“…All three known Orai isoforms are expressed in human lung MCs and participate in FcϵRI-mediated activation ( 6 ). Moreover, in a human MC line, LAD2 cells, shRNA-mediated silencing of STIM-1 results in significant decrease in MRGPRX2-mediated Ca 2+ mobilization and degranulation ( 25 ). Given that STIM-1 couples to Orai1 for Ca 2+ influx ( 26 ), we hypothesized that this CRAC channel contributes to SP-induced responses in human MCs.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Orai Channel Function Regulates Mas-Related G Protein-Coupled Receptor-Mediated Responses in Mast Cells

et al. 2022

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Mast cells (MCs) are tissue resident immune cells that play important roles in the pathogenesis of allergic disorders. These responses are mediated via the cross-linking of cell surface high affinity IgE receptor (FcϵRI) by antigen resulting in calcium (Ca2+) mobilization, followed by degranulation and release of proinflammatory mediators. In addition to FcϵRI, cutaneous MCs express Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MrgprB2). Activation of MRGPRX2/B2 by the neuropeptide substance P (SP) is implicated in neurogenic inflammation, chronic urticaria, mastocytosis and atopic dermatitis. Although Ca2+ entry is required for MRGPRX2/B2-mediated MC responses, the possibility that calcium release-activated calcium (CRAC/Orai) channels participate in these responses has not been tested. Lentiviral shRNA-mediated silencing of Orai1, Orai2 or Orai3 in a human MC line (LAD2 cells) resulted in partial inhibition of SP-induced Ca2+ mobilization, degranulation and cytokine/chemokine generation (TNF-α, IL-8, and CCL-3). Synta66, which blocks homo and hetero-dimerization of Orai channels, caused a more robust inhibition of SP-induced responses than knockdown of individual Orai channels. Synta66 also blocked SP-induced extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation and abrogated cytokine/chemokine production. It also inhibited SP-induced Ca2+ mobilization and degranulation in primary human skin MCs and mouse peritoneal MCs. Furthermore, Synta66 attenuated both SP-induced cutaneous vascular permeability and leukocyte recruitment in mouse peritoneum. These findings demonstrate that Orai channels contribute to MRGPRX2/B2-mediated MC activation and suggest that their inhibition could provide a novel approach for the modulation of SP-induced MC/MRGPRX2-mediated disorders.

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“…MRGPRX2 is a highly expressed GPCR in the DRG’s small-diameter neurons and is activated by CST-14 in a concentration-dependent manner [ 73 ]. Additionally, recent studies reported that CST-14 uses store-operated Ca 2+ entry via Stromal interaction molecule 1 (stim1) for MRGPRX2-induced MC activation, which leads to MC degranulation, Ca 2+ mobilization, and cytokine release in a concentration-dependent manner [ 104 ].…”

Section: Pharmacology Of Mas-related G Protein-coupled Receptors X 2 (Mrgprx2)mentioning

confidence: 99%

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Kumar

Duraisamy

Chow

2021

Cells

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Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

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Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

Cited by 34 publications

References 69 publications

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Inhibition of Orai Channel Function Regulates Mas-Related G Protein-Coupled Receptor-Mediated Responses in Mast Cells

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

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