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  • Recent studies showed that the activity of CK was significan


    Recent studies showed that the activity of CK2 was significantly reduced in ischemic stroke model rats, and cerebral I/R injury significantly decreased the expression of CK2α (Lee et al., 2004; Kim et al., 2012; Zhou et al., 2016). In addition, the dysregulation of CK2 is involved in ERS/UPR in non-neuronal IGF-1, human recombinant and the alteration of CK2 is associated with neuritogenesis (Lee et al., 2004; Kim et al., 2012; Zhou et al., 2016; Wang et al., 2005; Di Maira et al., 2008). For example, inhibition of CK2 could induce ERS/UPR in myeloma cells, while inhibition of CK2 reduces neuritogenesis (Hosoi et al., 2012; Manni et al., 2012). However, the role of CK2 in I/R injury-induced ERS/UPR and neuronal apoptosis has not been explored. In this study, we confirmed that CK2α was significantly reduced in ischemic stroke. Moreover, we found that CK2α reduction closely associated with cerebral I/R injury-induced p-eIF2α-ATF4-CHOP activation and neuronal apoptosis. Our previous studies demonstrated that apelin-13 attenuated neuronal apoptosis in ischemic stroke (Xin et al., 2015; Yan et al., 2015). Our recent work showed that apelin reduces I/R injury-induced CHOP elevation (Qiu et al., 2017). However, it remains elusive whether CK2-CHOP signaling is implicated in apelin-13\'s protective effect in ischemic stroke. We found that apelin-13 rescued I/R injury-induced reduction of CK2α expression, meanwhile, it inhibited the induction of p-eIF2α, ATF4 and CHOP expression. Consistently, apelin-13 attenuated neuronal apoptosis and reduced the infarct volume. Importantly, the rescue effects of apelin-13 were abolished by CK2α knockdown. It highly suggested that the protective effect of apelin-13 is mediated by CK2 dependent signaling. It is known that Gαi and Gαq mediate the effect of apelin-13 on different signaling pathways (Wu et al., 2017). For example, Gαi and Gαq contributes to phosphatidyl Inositol 3-kinase/serine/threonine kinase (PI3K/AKT) and phospholipase C beta-protein kinase C (PLCβ-PKC) activation, respectively (Chapman et al., 2014). Thus, we further determined that apelin-13\'s effect on neuronal apoptosis, CK2 and CK2-dependent CHOP signaling is mediated by Gαi or Gαq. We found that both Gαi and Gαq were implicated in apelin-13\'s protective effect on I/R-induced neuronal apoptosis and CK2-CHOP signaling. Our study demonstrated that apelin-13\'s protective effect is mediated by Gαi/Gαq-CK2 signaling. It suggested that apelin-13/apelin agonists and CK2 agonists may have therapeutic potential to increase the time-window of ischemic stroke treatment compared with the narrow time-window of thrombolytic therapy which is a widely applied clinical treatment for ischemic stroke. However, Gαi or Gαq could not be applied as the potential target for drug development. Gαi or Gαq mediates a plethora of functions independent of apelin-apelin receptor as more than a thousand G-protein coupled receptors are mediated by Gαi or Gαq protein (Hauser et al., 2018). Gαi/Gαq modulators may generate many side effects by its global effect on mediating the function of thousands of G-protein coupled receptors. Currently, drugs are only developed based on agonists and inhibitors of specific G-protein coupled receptors (Hauser et al., 2018). Therefore, apelin-13/apelin agonists and CK2 agonists, but not Gαi/Gαq agonists may have therapeutic potential for the treatment of ischemic stroke.
    Acknowledgements The present work was funded by National Natural Science Foundation of China (No. 816712276 and No. 81771147), Natural Science Foundation of Shandong Province (ZR2016HM30), Medical and Health Development Program of Shandong Province (2016WSB33025), 2015 Science and Technology Development Plan of Jining (No. 2015_79), International Cooperation Training Program of Outstanding Young Teachers of Jining Medical University (20160830), Youth Fund Project of Jining Medical University (No. JYQ14KJ19, No. JY2016KJ006Z), and College Students\' Science and Technology Innovation Training Program (No. 201610443048). The authors declare no competing financial interests.