PMID- 34830154
OWN - NLM
STAT- MEDLINE
DCOM- 20211220
LR  - 20240404
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 22
DP  - 2021 Nov 12
TI  - TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading 
      Depression Susceptibility and Trigeminovascular System Sensitization.
LID - 10.3390/ijms222212273 [doi]
LID - 12273
AB  - 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-1beta 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-1beta 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.
FAU - Nie, Lingdi
AU  - Nie L
AD  - Centre for Neuroscience, Department of Biological Sciences, Xi'an 
      Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China.
AD  - Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and 
      Integrative Biology, Liverpool L69 7ZB, UK.
FAU - Jiang, Liwen
AU  - Jiang L
AD  - Centre for Neuroscience, Department of Biological Sciences, Xi'an 
      Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China.
AD  - Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and 
      Integrative Biology, Liverpool L69 7ZB, UK.
FAU - Quinn, John P
AU  - Quinn JP
AUID- ORCID: 0000-0003-3551-7803
AD  - Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and 
      Integrative Biology, Liverpool L69 7ZB, UK.
FAU - Grubb, Blair D
AU  - Grubb BD
AD  - Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and 
      Integrative Biology, Liverpool L69 7ZB, UK.
FAU - Wang, Minyan
AU  - Wang M
AUID- ORCID: 0000-0002-7955-1627
AD  - Centre for Neuroscience, Department of Biological Sciences, Xi'an 
      Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China.
AD  - Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and 
      Integrative Biology, Liverpool L69 7ZB, UK.
LA  - eng
GR  - KSF-E-08/Key Program Special Fund in XJTLU/
PT  - Journal Article
DEP - 20211112
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Interleukin-1beta)
RN  - 0 (RNA, Messenger)
RN  - 0 (TRPA1 Cation Channel)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - JHB2QIZ69Z (Calcitonin Gene-Related Peptide)
SB  - IM
MH  - Animals
MH  - Calcitonin Gene-Related Peptide/metabolism
MH  - Cerebral Cortex/cytology/metabolism/*physiology
MH  - Cortical Spreading Depression/*physiology
MH  - Electrophysiology/methods
MH  - Gene Expression
MH  - Interleukin-1beta/genetics
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Migraine Disorders/metabolism/physiopathology
MH  - Neuroglia/metabolism/physiology
MH  - Neurons/metabolism/physiology
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats, Sprague-Dawley
MH  - TRPA1 Cation Channel/*metabolism
MH  - Trigeminal Ganglion/metabolism/*physiology
MH  - src-Family Kinases/*metabolism
MH  - Mice
MH  - Rats
PMC - PMC8620265
OTO - NOTNLM
OT  - IL-1beta
OT  - Src family kinases
OT  - calcitonin gene-related peptide
OT  - cortical spreading depression
OT  - migraine
OT  - neuroinflammation
OT  - protein kinase A
OT  - transient receptor potential ankyrin 1
OT  - trigeminal ganglia
OT  - trigeminovascular system
COIS- The authors declare no potential conflicts of interest with respect to the 
      research, authorship and/or publication of this article.
EDAT- 2021/11/28 06:00
MHDA- 2021/12/21 06:00
PMCR- 2021/11/12
CRDT- 2021/11/27 01:11
PHST- 2021/09/27 00:00 [received]
PHST- 2021/11/06 00:00 [revised]
PHST- 2021/11/06 00:00 [accepted]
PHST- 2021/11/27 01:11 [entrez]
PHST- 2021/11/28 06:00 [pubmed]
PHST- 2021/12/21 06:00 [medline]
PHST- 2021/11/12 00:00 [pmc-release]
AID - ijms222212273 [pii]
AID - ijms-22-12273 [pii]
AID - 10.3390/ijms222212273 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Nov 12;22(22):12273. doi: 10.3390/ijms222212273.