Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors



Bu, Fan, Nie, Lingdi, Quinn, John P ORCID: 0000-0003-3551-7803 and Wang, Minyan
(2020) Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (4). E1269-.

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Abstract

Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K<sup>+</sup> to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A-receptor antagonist, NVP-AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK-Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP-AAM077 reduced elevation of ipsilateral SFK-Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.

Item Type: Article
Uncontrolled Keywords: cortical spreading depression, migraine, pannexin-1, sarcoma family kinases, NR2A
Depositing User: Symplectic Admin
Date Deposited: 27 Mar 2020 09:54
Last Modified: 02 Feb 2024 13:41
DOI: 10.3390/ijms21041269
Open Access URL: https://www.mdpi.com/1422-0067/21/4/1269
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3079710