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...

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Autores principales:	Lingdi Nie, Liwen Jiang, John P. Quinn, Blair D. Grubb, Minyan Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	migraine transient receptor potential ankyrin 1 Src family kinases cortical spreading depression trigeminovascular system protein kinase A Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/7e720fcaeea84a5a814f6839da0a01de
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spelling	oai:doaj.org-article:7e720fcaeea84a5a814f6839da0a01de2021-11-25T17:54:55ZTRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization10.3390/ijms2222122731422-00671661-6596https://doaj.org/article/7e720fcaeea84a5a814f6839da0a01de2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12273https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Transient 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.Lingdi NieLiwen JiangJohn P. QuinnBlair D. GrubbMinyan WangMDPI AGarticlemigrainetransient receptor potential ankyrin 1Src family kinasescortical spreading depressiontrigeminovascular systemprotein kinase ABiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12273, p 12273 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	migraine transient receptor potential ankyrin 1 Src family kinases cortical spreading depression trigeminovascular system protein kinase A Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	migraine transient receptor potential ankyrin 1 Src family kinases cortical spreading depression trigeminovascular system protein kinase A Biology (General) QH301-705.5 Chemistry QD1-999 Lingdi Nie Liwen Jiang John P. Quinn Blair D. Grubb Minyan Wang TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization
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	article
author	Lingdi Nie Liwen Jiang John P. Quinn Blair D. Grubb Minyan Wang
author_facet	Lingdi Nie Liwen Jiang John P. Quinn Blair D. Grubb Minyan Wang
author_sort	Lingdi Nie
title	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_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_sort	trpa1-mediated src family kinases activity facilitates cortical spreading depression susceptibility and trigeminovascular system sensitization
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7e720fcaeea84a5a814f6839da0a01de
work_keys_str_mv	AT lingdinie trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT liwenjiang trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT johnpquinn trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT blairdgrubb trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization AT minyanwang trpa1mediatedsrcfamilykinasesactivityfacilitatescorticalspreadingdepressionsusceptibilityandtrigeminovascularsystemsensitization
_version_	1718411870698733568

TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization

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