| First Author | Freitas-Andrade M | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 4 | Pages | 916-935 |
| PubMed ID | 30872361 | Mgi Jnum | J:275170 |
| Mgi Id | MGI:6305926 | Doi | 10.1084/jem.20171452 |
| Citation | Freitas-Andrade M, et al. (2019) Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke. J Exp Med 216(4):916-935 |
| abstractText | Connexin43 (Cx43) function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of wild-type (WT) and knock-in Cx43 with serine to alanine mutations at the protein kinase C (PKC) site Cx43(S368A), the casein kinase 1 (CK1) sites Cx43(S325A/328Y/330A), and the mitogen-activated protein kinase (MAPK) sites Cx43(S255/262/279/282A) (MK4) on a permanent middle cerebral artery occlusion (pMCAO) stroke model. We demonstrate that MK4 transgenic animals exhibit a significant decrease in infarct volume that was associated with improvement in behavioral performance. An increase in astrocyte reactivity with a concomitant decrease in microglial reactivity was observed in MK4 mice. In contrast to WT, MK4 astrocytes displayed reduced Cx43 hemichannel activity. Pharmacological blockade of Cx43 hemichannels with TAT-Gap19 also significantly decreased infarct volume in WT animals. This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function. |
