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Open AccessArticle

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

by Fan Bu 1,2,†, Lingdi Nie 1,2,†, John P Quinn 2 and Minyan Wang 1,*
1
Department of Biological Sciences, Centre for Neuroscience, Xi’an Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China
2
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 7ZB, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(4), 1269; https://doi.org/10.3390/ijms21041269
Received: 23 January 2020 / Revised: 9 February 2020 / Accepted: 11 February 2020 / Published: 13 February 2020
(This article belongs to the Section Molecular Neurobiology)
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+ 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. View Full-Text
Keywords: cortical spreading depression; migraine; pannexin-1; sarcoma family kinases; NR2A cortical spreading depression; migraine; pannexin-1; sarcoma family kinases; NR2A
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Bu, F.; Nie, L.; Quinn, J.P.; Wang, M. Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors. Int. J. Mol. Sci. 2020, 21, 1269.

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