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In previous studies, acidic stimulation leads to rapid increase in intracellular calcium in neurons. However, it remains largely unclear how a prolonged acidosis alters neuronal signaling. In our previous study, we found that GPR68-mediated PKC activities are protective against acidosis-induced injury in cortical slices. Here, we first asked whether the same principle holds true in organotypic hippocampal slices. Our data showed that 1-h pH 6 induced PKC phosphorylation in a GPR68-dependent manner. Go6983, a PKC inhibitor worsened acidosis-induced neuronal injury in wild type (WT) but had no effect in GPR68<jats:sup>\u2212\/\u2212<\/jats:sup> slices. Next, to gain greater insights into acid signaling in brain tissue, we treated organotypic hippocampal slices with pH 6 for 1-h and performed a kinome profiling analysis by Western blot. Acidosis had little effect on cyclin-dependent kinase (CDK) or casein kinase 2 activity, two members of the CMGC family, or Ataxia telangiectasia mutated (ATM)\/ATM and RAD3-related (ATR) activity, but reduced the phosphorylation of MAPK\/CDK substrates. In contrast, acidosis induced the activation of CaMKII\u03b1, PKA, and Akt. Besides these serine\/threonine kinases, acidosis also induced tyrosine phosphorylation. Since GPR68 is widely expressed in brain neurons, we asked whether GPR68 contributes to acidosis-induced signaling. Deleting GPR68 had no effect on acidosis-induced CaMKII phosphorylation, attenuated that of phospho-Akt and phospho-PKA substrates, while abolishing acidosis-induced tyrosine phosphorylation. These data demonstrate that prolonged acidosis activates a network of signaling cascades, mediated by AGC kinases, CaMKII, and tyrosine kinases. GPR68 is the primary mediator for acidosis-induced activation of PKC and tyrosine phosphorylation, while both GPR68-dependent and -independent mechanisms contribute to the activation of PKA and Akt.<\/jats:p>","DOI":"10.3389\/fnins.2021.692217","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T04:46:02Z","timestamp":1621917962000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["GPR68 Contributes to Persistent Acidosis-Induced Activation of AGC Kinases and Tyrosine Phosphorylation in Organotypic Hippocampal Slices"],"prefix":"10.3389","volume":"15","author":[{"given":"Guokun","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-ming","family":"Zha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1016\/j.bbapap.2013.03.010","article-title":"AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases","volume":"1834","author":"Arencibia","year":"2013","journal-title":"Biochim. 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