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Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

期刊

BIOMOLECULES
卷 10, 期 11, 页码 -

出版社

MDPI
DOI: 10.3390/biom10111578

关键词

connexin43; seizures; epilepsy; gap junctions; hemichannels; astrocytes; mimetic peptides

资金

  1. Vrije Universiteit Brussel [SPR49/OZR2102]
  2. Ghent University Special Research Fund
  3. Geneeskundige Stichting Koningin Elisabeth [STI.DI2.2017.0004.01]
  4. European Research Council
  5. Fund for Scientific Research Flanders-Belgium [G.0A82.13N, G.0527.18N]
  6. University Hospital of the Vrije Universiteit Brussel-Belgium (Willy Gepts Fonds UZ-VUB)

向作者/读者索取更多资源

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.

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