| First Author | Ye J | Year | 2019 |
| Journal | Mol Neurobiol | Volume | 56 |
| Issue | 3 | Pages | 2123-2136 |
| PubMed ID | 29992531 | Mgi Jnum | J:319283 |
| Mgi Id | MGI:6863504 | Doi | 10.1007/s12035-018-1198-2 |
| Citation | Ye J, et al. (2019) Ischemic Injury-Induced CaMKIIdelta and CaMKIIgamma Confer Neuroprotection Through the NF-kappaB Signaling Pathway. Mol Neurobiol 56(3):2123-2136 |
| abstractText | Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the CaMKII family in neuronal survival during I/R. Our data indicated that CAMK2D/CaMKIIdelta and CAMK2G/CaMKIIgamma were selectively upregulated in a time-dependent manner at both transcriptional and protein levels after acute ischemia. Overexpression of CaMKIIdelta promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar to CaMKIIdelta, knockdown of CAMKIIgamma resulted in significant neuronal death after I/R. We further identified CaMKIIdelta2 as the subtype that is selectively induced by I/R in primary neurons. The induction of CaMKIIdelta was controlled in part by a pair of long non-coding RNAs (lncRNAs), C2dat1 and C2dat2. C2dat2, similar to C2dat1, was upregulated by I/R and cooperated with C2dat1 to modulate CaMKIIdelta expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKIIdelta expression and decreased neuronal survival but did not affect the levels of CaMKIIgamma, indicating specific targeting of CAMK2D by C2dat1/2. Mechanistically, I/R-induced CaMKIIdelta and CaMKIIgamma caused the upregulation of IKKalpha/beta and further activation of the NF-kappaB signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-kappaB in mice increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/IkappaBalpha/NF-kappaB signaling axis. In summary, CaMKIIdelta and CaMKIIgamma are novel I/R-induced genes that promote neuronal survival during ischemic injury. The upregulation of these CaMKII kinases led to activation of the NF-kappaB signaling pathway, which protects neurons from ischemic damage. |
