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Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke

(2019) JOURNAL OF EXPERIMENTAL MEDICINE. 216(4). p.916-935
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Abstract
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.
Keywords
JUNCTIONAL INTERCELLULAR COMMUNICATION, ASTROCYTIC GAP-JUNCTIONS, FOCAL CEREBRAL-ISCHEMIA, INFARCT VOLUME, FUNCTIONAL RECOVERY, EFFECTIVE REDUCTION, SIGNALING PATHWAY, GENE-EXPRESSION, RODENT MODEL, BRAIN

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MLA
Freitas-Andrade, Moises et al. “Targeting MAPK Phosphorylation of Connexin43 Provides Neuroprotection in Stroke.” JOURNAL OF EXPERIMENTAL MEDICINE 216.4 (2019): 916–935. Print.
APA
Freitas-Andrade, M., Wang, N., Bechberger, J. F., De Bock, M., Lampe, P. D., Leybaert, L., & Naus, C. C. (2019). Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke. JOURNAL OF EXPERIMENTAL MEDICINE, 216(4), 916–935.
Chicago author-date
Freitas-Andrade, Moises, Nan Wang, John F Bechberger, Marijke De Bock, Paul D Lampe, Luc Leybaert, and Christian C Naus. 2019. “Targeting MAPK Phosphorylation of Connexin43 Provides Neuroprotection in Stroke.” Journal of Experimental Medicine 216 (4): 916–935.
Chicago author-date (all authors)
Freitas-Andrade, Moises, Nan Wang, John F Bechberger, Marijke De Bock, Paul D Lampe, Luc Leybaert, and Christian C Naus. 2019. “Targeting MAPK Phosphorylation of Connexin43 Provides Neuroprotection in Stroke.” Journal of Experimental Medicine 216 (4): 916–935.
Vancouver
1.
Freitas-Andrade M, Wang N, Bechberger JF, De Bock M, Lampe PD, Leybaert L, et al. Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke. JOURNAL OF EXPERIMENTAL MEDICINE. 2019;216(4):916–35.
IEEE
[1]
M. Freitas-Andrade et al., “Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 216, no. 4, pp. 916–935, 2019.
@article{8608349,
  abstract     = {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.},
  author       = {Freitas-Andrade, Moises and Wang, Nan and Bechberger, John F and De Bock, Marijke and Lampe, Paul D and Leybaert, Luc and Naus, Christian C},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  keywords     = {JUNCTIONAL INTERCELLULAR COMMUNICATION,ASTROCYTIC GAP-JUNCTIONS,FOCAL CEREBRAL-ISCHEMIA,INFARCT VOLUME,FUNCTIONAL RECOVERY,EFFECTIVE REDUCTION,SIGNALING PATHWAY,GENE-EXPRESSION,RODENT MODEL,BRAIN},
  language     = {eng},
  number       = {4},
  pages        = {916--935},
  title        = {Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke},
  url          = {http://dx.doi.org/10.1084/jem.20171452},
  volume       = {216},
  year         = {2019},
}

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