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Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells
Intracellular Ca(2+) and cAMP typically cause opposing effects on airway smooth muscle contraction. Receptors that stimulate these pathways are therapeutic targets in asthma and chronic obstructive pulmonary disease. However, the interactions between different G protein-coupled receptors (GPCRs) tha...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893132/ https://www.ncbi.nlm.nih.gov/pubmed/29604964 http://dx.doi.org/10.1016/j.ceca.2017.12.002 |
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author | Dale, Philippa Head, Victoria Dowling, Mark R. Taylor, Colin W. |
author_facet | Dale, Philippa Head, Victoria Dowling, Mark R. Taylor, Colin W. |
author_sort | Dale, Philippa |
collection | PubMed |
description | Intracellular Ca(2+) and cAMP typically cause opposing effects on airway smooth muscle contraction. Receptors that stimulate these pathways are therapeutic targets in asthma and chronic obstructive pulmonary disease. However, the interactions between different G protein-coupled receptors (GPCRs) that evoke cAMP and Ca(2+) signals in human bronchial airway smooth muscle cells (hBASMCs) are poorly understood. We measured Ca(2+) signals in cultures of fluo-4-loaded hBASMCs alongside measurements of intracellular cAMP using mass spectrometry or [(3)H]-adenine labeling. Interactions between the signaling pathways were examined using selective ligands of GPCRs, and inhibitors of Ca(2+) and cAMP signaling pathways. Histamine stimulated Ca(2+) release through inositol 1,4,5-trisphosphate (IP(3)) receptors in hBASMCs. β(2)-adrenoceptors, through cAMP and protein kinase A (PKA), substantially inhibited histamine-evoked Ca(2+) signals. Responses to other Ca(2+)-mobilizing stimuli were unaffected by cAMP (carbachol and bradykinin) or minimally affected (lysophosphatidic acid). Prostaglandin E(2) (PGE(2)), through EP(2) and EP(4) receptors, stimulated formation of cAMP and inhibited histamine-evoked Ca(2+) signals. There was no consistent relationship between the inhibition of Ca(2+) signals and the amounts of intracellular cAMP produced by different stimuli. We conclude that β-adrenoceptors, EP(2) and EP(4) receptors, through cAMP and PKA, selectively inhibit Ca(2+) signals evoked by histamine in hBASMCs, suggesting that PKA inhibits an early step in H(1) receptor signaling. Local delivery of cAMP within hyperactive signaling junctions mediates the inhibition. |
format | Online Article Text |
id | pubmed-5893132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-58931322018-05-01 Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells Dale, Philippa Head, Victoria Dowling, Mark R. Taylor, Colin W. Cell Calcium Article Intracellular Ca(2+) and cAMP typically cause opposing effects on airway smooth muscle contraction. Receptors that stimulate these pathways are therapeutic targets in asthma and chronic obstructive pulmonary disease. However, the interactions between different G protein-coupled receptors (GPCRs) that evoke cAMP and Ca(2+) signals in human bronchial airway smooth muscle cells (hBASMCs) are poorly understood. We measured Ca(2+) signals in cultures of fluo-4-loaded hBASMCs alongside measurements of intracellular cAMP using mass spectrometry or [(3)H]-adenine labeling. Interactions between the signaling pathways were examined using selective ligands of GPCRs, and inhibitors of Ca(2+) and cAMP signaling pathways. Histamine stimulated Ca(2+) release through inositol 1,4,5-trisphosphate (IP(3)) receptors in hBASMCs. β(2)-adrenoceptors, through cAMP and protein kinase A (PKA), substantially inhibited histamine-evoked Ca(2+) signals. Responses to other Ca(2+)-mobilizing stimuli were unaffected by cAMP (carbachol and bradykinin) or minimally affected (lysophosphatidic acid). Prostaglandin E(2) (PGE(2)), through EP(2) and EP(4) receptors, stimulated formation of cAMP and inhibited histamine-evoked Ca(2+) signals. There was no consistent relationship between the inhibition of Ca(2+) signals and the amounts of intracellular cAMP produced by different stimuli. We conclude that β-adrenoceptors, EP(2) and EP(4) receptors, through cAMP and PKA, selectively inhibit Ca(2+) signals evoked by histamine in hBASMCs, suggesting that PKA inhibits an early step in H(1) receptor signaling. Local delivery of cAMP within hyperactive signaling junctions mediates the inhibition. Elsevier 2018-05 /pmc/articles/PMC5893132/ /pubmed/29604964 http://dx.doi.org/10.1016/j.ceca.2017.12.002 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dale, Philippa Head, Victoria Dowling, Mark R. Taylor, Colin W. Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title | Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title_full | Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title_fullStr | Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title_full_unstemmed | Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title_short | Selective inhibition of histamine-evoked Ca(2+) signals by compartmentalized cAMP in human bronchial airway smooth muscle cells |
title_sort | selective inhibition of histamine-evoked ca(2+) signals by compartmentalized camp in human bronchial airway smooth muscle cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893132/ https://www.ncbi.nlm.nih.gov/pubmed/29604964 http://dx.doi.org/10.1016/j.ceca.2017.12.002 |
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