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    Previously, we showed that Src-mediated EGF receptor transactivation/ERK activation mediates ammonia-induced astrocyte swelling, which represents a major component of brain edema in hyperammonemic disorders. Here, we tested the role of PKC in the induction of this signaling pathway and its involvement in ammonia-mediated cell swelling. We found that incubating astrocytes with bisindolylmaleimide (BIM, an inhibitor of classical and novel PKC isoforms) or rottlerin, a PKCδ-specific inhibitor, attenuated the ammonia-induced phosphorylation of EGFR, while GF109203X had no effect on this pathway. We further found that BIM or rottlerin pretreatment inhibited the ammonia-induced phosphorylation of Src and that ammonia significantly increased the level of PKCδ pulled down by a Src antibody. AG1478, a specific EGFR kinase activity inhibitor, effectively inhibited phosphorylation at Tyr1068 but had no discernable effect on phosphorylation at Tyr845. Moreover, BIM or rottlerin abrogated ammonia-induced ERK phosphorylation. BIM-, rottlerin-, or GF109203X-treated astrocytes showed a significant reduction in cell swelling compared to that observed after treatment with ammonia alone. Finally, it was found that AG1478 attenuated ammonia-induced PKCα translocation to the particulate fraction. Taken together, our results indicate that PKCδ mediates ammonia-induced astrocyte swelling by activating Src and downstream EGF receptor/ERK signaling, which may contribute to the pathogenesis of neuropsychiatric disorders associated with hyperammonemia.

    Citation

    Guizhi Jia, Rui Wang, Yi Yue, Hongliang Dai. Activation of Protein Kinase Cδ Contributes to the Induction of Src/EGF Receptor/ERK Signaling in Ammonia-treated Astrocytes. Journal of molecular neuroscience : MN. 2020 Jul;70(7):1110-1119

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    PMID: 32125625

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