Targeting gap junction in epilepsy: Perspectives and challenges

Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy

“…In vitro experiments revealed that α4β2-nAChR activation can decrease endothelial intercellular communication via the downregulation of connexin 43 (Cx43) [24]. Connexin is a family of 21 protein isoforms, and 11 connexin isoforms are expressed in the central nervous system [25][26][27]. Six connexin proteins assemble to form a homomeric/heteromeric connexon.…”

“…Six connexin proteins assemble to form a homomeric/heteromeric connexon. Two connexon in two neighboring cells (including neuron, astrocyte, oligodendrocyte and microglia) form a gap-junction channel with an aqueous pore and charged surface walls [25][26][27]. A single connexon contributes to chemical connection between intra-and extra-cellular spaces as hemichannels [25][26][27].…”

“…Two connexon in two neighboring cells (including neuron, astrocyte, oligodendrocyte and microglia) form a gap-junction channel with an aqueous pore and charged surface walls [25][26][27]. A single connexon contributes to chemical connection between intra-and extra-cellular spaces as hemichannels [25][26][27]. Cx43 is the most widely expressed and predominantly expressed isoform in the central nervous system, including in astrocytes [28,29].…”

“…Cx43 is the most widely expressed and predominantly expressed isoform in the central nervous system, including in astrocytes [28,29]. Accumulating evidence indicates that connexin is crucial to the coordination and maintenance of physiologic activity including neuronal excitability, synaptic plasticity, tripartite synaptic transmission and homeostasis maintenance in the central nervous system [26,27]. Furthermore, the expression of Cx43 is increased in glia but not in neurone in animal models and patients with epilepsy [30].…”

“…Furthermore, the expression of Cx43 is increased in glia but not in neurone in animal models and patients with epilepsy [30]. In particular, inhibitors of connexin channels can prevent the onset of epileptic seizures [26,31,32]. Recently, we demonstrated that an atypical antipsychotic, clozapine, was able to increase hemichannel activity as well as Cx43 expression in a concentration dependent manner in the plasma membrane of astrocytes [33,34].…”