Cargando…

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

Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca(2+)) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein...

Descripción completa

Detalles Bibliográficos
Autores principales: Occhiuto, Christopher J., Kammala, Ananth K., Yang, Canchai, Nellutla, Rithvik, Garcia, Marco, Gomez, Gregorio, Subramanian, Hariharan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985555/
https://www.ncbi.nlm.nih.gov/pubmed/32038646
http://dx.doi.org/10.3389/fimmu.2019.03143
_version_ 1783491827863650304
author Occhiuto, Christopher J.
Kammala, Ananth K.
Yang, Canchai
Nellutla, Rithvik
Garcia, Marco
Gomez, Gregorio
Subramanian, Hariharan
author_facet Occhiuto, Christopher J.
Kammala, Ananth K.
Yang, Canchai
Nellutla, Rithvik
Garcia, Marco
Gomez, Gregorio
Subramanian, Hariharan
author_sort Occhiuto, Christopher J.
collection PubMed
description Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca(2+)) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca(2+) levels; however, the Ca(2+) mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca(2+) entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.
format Online
Article
Text
id pubmed-6985555
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-69855552020-02-07 Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions Occhiuto, Christopher J. Kammala, Ananth K. Yang, Canchai Nellutla, Rithvik Garcia, Marco Gomez, Gregorio Subramanian, Hariharan Front Immunol Immunology Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca(2+)) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca(2+) levels; however, the Ca(2+) mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca(2+) entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans. Frontiers Media S.A. 2020-01-21 /pmc/articles/PMC6985555/ /pubmed/32038646 http://dx.doi.org/10.3389/fimmu.2019.03143 Text en Copyright © 2020 Occhiuto, Kammala, Yang, Nellutla, Garcia, Gomez and Subramanian. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Occhiuto, Christopher J.
Kammala, Ananth K.
Yang, Canchai
Nellutla, Rithvik
Garcia, Marco
Gomez, Gregorio
Subramanian, Hariharan
Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title_full Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title_fullStr Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title_full_unstemmed Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title_short Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
title_sort store-operated calcium entry via stim1 contributes to mrgprx2 induced mast cell functions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985555/
https://www.ncbi.nlm.nih.gov/pubmed/32038646
http://dx.doi.org/10.3389/fimmu.2019.03143
work_keys_str_mv AT occhiutochristopherj storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT kammalaananthk storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT yangcanchai storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT nellutlarithvik storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT garciamarco storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT gomezgregorio storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions
AT subramanianhariharan storeoperatedcalciumentryviastim1contributestomrgprx2inducedmastcellfunctions