Src family kinases activity is required for transmitting purinergic P2X7 receptor signaling in cortical spreading depression and neuroinflammation

The Journal of Headache and Pain

Dongqing Ma¹  Minyan Wang¹  Lingdi Nie¹  John P. Quinn² 

[1] Department of Biological Sciences, Centre for Neuroscience, Xi’an Jiaotong-Liverpool University (XJTLU), 111 Ren Ai Road, Suzhou Industrial Park, 215123, Suzhou, P. R. China;Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, L69 7ZB, Liverpool, UK;Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, L69 7ZB, Liverpool, UK;

关键词: Migraine;    cortical spreading depression;    P2X7 receptor;    Src family kinases;    glutamatergic pathway;    neuroinflammation;   

DOI  :  10.1186/s10194-021-01359-8

来源: Springer

【 摘 要 】

BackgroundPurinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and neuroinflammation after CSD.MethodsCSD was recorded using electrophysiology in rats and intrinsic optical imaging in mouse brain slices. Cortical IL-1β and TNFα mRNA levels were detected using qPCR. Glutamate release from mouse brain slices was detected using glutamate assay.ResultsThe data showed that deactivation of SFKs by systemic injection of PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1β and TNF-α gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor and SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, IL-1β gene expression and glutamate release after CSD induction were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA, and disrupting the Fyn-NMDA interaction using TAT-Fyn (39-57) but not disrupting Src-NMDA receptor interaction using TAT-Src (40-49) reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD.ConclusionThis study reveals that SFKs activity transmits P2X7 receptor signaling to facilitate CSD propagation via glutamatergic pathway and promote neuroinflammation, which is of particular relevance to migraine.

【 授权许可】

CC BY