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Tachykinin-1 receptor antagonism suppresses substance-P- and compound 48/80-induced mast cell activation from rat mast cells expressing functional mas-related GPCR B3

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Abstract

Objective

Mice and rats are important animal models for mast cell (MC) study. However, rat Mas-related-GPCR-B3 receptor (MRGPRB3) has been less studied than its mouse counterpart. Therefore, we aimed to characterize rat MRGPRB3.

Methods

Mrgprb3 mRNA expression was assessed in peritoneal cells (RPCs) and peritoneal MCs (RPMCs) of wild-type rats, RPCs of MC-deficient rats, and RBL-2H3 cells by reverse-transcriptase polymerase chain reaction (RT-PCR). RPMCs, MRGPRX2-transfected and non-transfected RBL-2H3 cells were activated by 15–30 min incubation with DNP-BSA, substance-P (SP), or compound-48/80. L732138 or CP96344 was used as a tachykinin/neurokinin-1-receptor antagonist. Histamine release from MCs was measured by HPLC fluorometry.

Results

Mrgprb3 mRNA expression was found in all cells, with the highest level in wild-type RPCs. All cells responded to DNP-BSA, but only MRGPRX2-transfected-RBL-2H3 cells and RPMCs responded to all activators. L732138 (0.1–10 μM) and CP96344 (1–100 μM) suppressed SP (10 μM)-induced RPMC activation. L732138 inhibition was dose independent, whereas CP96344 inhibition occurred in a dose-dependent manner. Additionally, only CP96344 suppressed SP (100 μM)- and compound-48/80 (10 μg/mL)-induced RPMC activation.

Conclusions

RPMCs expressing functional MRGPRB3 response upon MRGPRX2 ligands to regulated MC-mediated activities. It`s provide novel insights for future pseudo-allergic studies in rodents.

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Acknowledgements

Thanks to Ms. Takemasa Erika and Dr. Takeshi Kiyoi for their technical support.

Author information

Author notes

  1. Muhammad N. A. Sahid

    Present address: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia

Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Medicine, Ehime University, Toon, Ehime, 791-0295, Japan

    Muhammad N. A. Sahid, Shuang Liu, Masaki Mogi & Kazutaka Maeyama

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Contributions

Conceptualization: MNAS, KM; methodology: MNAS, KM; investigation: MNAS, SL; writing—original draft: MNAS; writing—review and editing: MNAS, KM; supervision: KM, MM.

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Correspondence to Muhammad N. A. Sahid.

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Electronic supplementary material

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Supplementary file1 (DOCX 65 kb)

Supplementary file2 (DOCX 66 kb)

11_2020_1319_MOESM3_ESM.pdf

Supplementary Fig. 1 Prediction of transmembrane region of MRGPR family analyzed by HMMTP version 2.0 (http://www.enzim.hu/hmmtop/). (A) Mouse MRGPRB2 protein (NCBI Accession: EDL22965), (B) human MRGPRX2 protein (NCBI Accession: ACG60653), (C) rat MRGPRB3 protein (NCBI Accession: XP_001077174.2). Upper case (O): indicating outer tail region; lower case (o): outer loop or outer tail that close to the cell membrane; upper case (H): transmembrane region; upper case (I): intracellular tail region; and lower case (i): intracellular loop or intracellular tail that close to the cell membrane (PDF 1958 kb)

11_2020_1319_MOESM4_ESM.pdf

Supplementary Fig. 2 Prediction of transmembrane region of MRGPR family analyzed by Protter version 1.0 (http://wlab.ethz.ch/protter/). (A) Mouse MRGPRB2 protein (Uniprot ID: Q3KNA1), (B) human MRGPRX2 protein (Uniprot ID: Q96LB1), and (C) rat MRGPRB3 protein (Uniprot ID: F1LLV4) (PDF 126 kb)

11_2020_1319_MOESM5_ESM.pdf

Supplementary Fig. 3 Prediction of transmembrane region of MRGPR family analyzed by RbDe (http://icb.med.cornell.edu/services/rbde/diagrams). (A) Mouse MRGPRB2 protein (Uniprot ID: Q3KNA1), (B) human MRGPRX2 protein (Uniprot ID: Q96LB1), and (C) rat MRGPRB3 protein (Uniprot ID: F1LLV4) (PDF 2399 kb)

11_2020_1319_MOESM6_ESM.pdf

Supplementary Fig. 4 Histamine release induced by compound-48/80 and SP. Substance-P dose-dependently (1-1000 µM) increased histamine release in RPMCs (a). High concentration compound-48/80 (100 µg/mL) induced histamine release in RBL-2H3 cells (b). Data are expressed as mean + S.E.M. from triplicate experiments. (#) Indicates significant difference vs lower dose group, p < 0.0001 (PDF 38 kb)

11_2020_1319_MOESM7_ESM.pdf

Supplementary Fig. 5 High concentration of L732138 and CP96344 increases histamine release from RPMCs. Low concentration of TACR1 antagonist L732138 (up to 10 µM) did not induce histamine release from RPMCs (a). Low concentration of TACR1 antagonist CP96344 (up to 100 µM) did not induce histamine release from RPMCs (b). Data are expressed as mean + S.E.M. from triplicate experiments. (#) Indicates significant difference vs lower dose group with p < 0.0001, (##) p < 0.001 (PDF 34 kb)

11_2020_1319_MOESM8_ESM.pdf

Supplementary Fig. 6 Ciprofloxacin induces histamine release from RPMCs. Ciprofloxacin-induced histamine release followed the method for MC activation by compound 48/80, as described in the Methods section. Data are expressed as mean + S.E.M. from triplicate experiments. (#) Indicates significant difference vs dose group, p < 0.0001 (PDF 25 kb)

11_2020_1319_MOESM9_ESM.pdf

Supplementary Fig. 7 Structure of tachykinin receptor 1 (TACR1) antagonists L732138 (a) and CP96344 (b). Box with dashed line highlights the structure mimicking tetrahydroisoquinoline (THIQ) (PDF 165 kb)

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Sahid, M.N.A., Liu, S., Mogi, M. et al. Tachykinin-1 receptor antagonism suppresses substance-P- and compound 48/80-induced mast cell activation from rat mast cells expressing functional mas-related GPCR B3. Inflamm. Res. 69, 289–298 (2020). https://doi.org/10.1007/s00011-020-01319-z

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