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

Nie, Lingdi, Jiang, Liwen, Quinn, John P ORCID: 0000-0003-3551-7803, Grubb, Blair D and Wang, Minyan (2021) TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22 (22). 12273-. ISSN 1661-6596, 1422-0067

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	migraine, transient receptor potential ankyrin 1, Src family kinases, cortical spreading depression, trigeminovascular system, protein kinase A, calcitonin gene-related peptide, IL-1 beta, neuroinflammation, trigeminal ganglia
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	28 Jan 2022 09:36
Last Modified:	23 May 2026 06:26
DOI:	10.3390/ijms222212273
Open Access URL:	https://doi.org/10.3390/ijms222212273
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3147758
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