Cargando…
TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization
Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620265/ https://www.ncbi.nlm.nih.gov/pubmed/34830154 http://dx.doi.org/10.3390/ijms222212273 |
_version_ | 1784605179004321792 |
---|---|
author | Nie, Lingdi Jiang, Liwen Quinn, John P. Grubb, Blair D. Wang, Minyan |
author_facet | Nie, Lingdi Jiang, Liwen Quinn, John P. Grubb, Blair D. Wang, Minyan |
author_sort | Nie, Lingdi |
collection | PubMed |
description | Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1β gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1β mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14–22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization. |
format | Online Article Text |
id | pubmed-8620265 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86202652021-11-27 TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization Nie, Lingdi Jiang, Liwen Quinn, John P. Grubb, Blair D. Wang, Minyan Int J Mol Sci Article Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1β gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1β mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14–22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization. MDPI 2021-11-12 /pmc/articles/PMC8620265/ /pubmed/34830154 http://dx.doi.org/10.3390/ijms222212273 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nie, Lingdi Jiang, Liwen Quinn, John P. Grubb, Blair D. Wang, Minyan TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title | TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title_full | TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title_fullStr | TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title_full_unstemmed | TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title_short | TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization |
title_sort | trpa1-mediated src family kinases activity facilitates cortical spreading depression susceptibility and trigeminovascular system sensitization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620265/ https://www.ncbi.nlm.nih.gov/pubmed/34830154 http://dx.doi.org/10.3390/ijms222212273 |
work_keys_str_mv | AT nielingdi trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT jiangliwen trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT quinnjohnp trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT grubbblaird trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT wangminyan trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization |