Research progress of connexins in epileptogensis

Abstract

Epilepsy, a chronic neurological disorder, is characterized by dysfunction in neural networks. Gap junctions and hemichannels, which are integral to the astrocyte connection network, play a critical role in epilepsy. Connexins, the components of astrocyte gap junctions and hemichannels, can be activated to transfer glutamate, adenosine triphosphate, and other chemicals, potentially leading to seizures. Connexins therefore hold significant potential for epilepsy treatment. This review focuses on connexin 43 and provides a brief overview of other connexins and pannexin 1. Understanding the relationship between connexins and epilepsy offers theoretical support for developing new antiseizure medications.

Keywords: Connexin; Epilepsy; Gap junction; Hemichannel; Wnt pathway.

Fig. 1

The structure of connexins, connexin-based hemichannel and connexin-based gap junctions. This figure showed the structure of connexins, connexin-based hemichannel and connexin-based gap junctions. a Connexin-based hemichannel: the hemichannel is formed by six connexins (one connexin drawn in the dotted line) arranged side by side, forming a channel that can only accommodate molecules of 1 kDa. b Connexin tetrasaccharide transmembrane (TM) domain protein: TM1 and TM2 or TM3 and TM4 are connected by extracellular loops (E1 or E2, respectively). TM2 and TM3 are connected by cellular loops (CL). TM1 ligates the N-terminus of the entire connexin intracellularly, and TM4 ligates the C-terminus of the entire connexin intracellularly. c The process of calcium transfer between astrocytes through Cx43-based gap junctions. After an extensive influx of calcium, the concentration of calcium in astrocytes increases, which can facilitate cell-to-cell diffusion through Cx43-based gap junctions

Fig. 2

The epileptogenic mechanism of Cx43. This figure showed the epileptogenic mechanism of Cx43. Cx43-based hemichannels are involved during seizures. After receiving external stimuli, the body can activate a Cx43-based hemichannel by changing the pH in the body or producing reactive oxygen species (ROS), through which calcium then flows inward. A wide influx of calcium can form a whole wave of calcium and participate in the formation of seizures. In addition, Cx43-based hemichannels can release substances such as glutamate, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and D-serine upon activation. Among them, ATP, NAD and D-serine can participate in the inflammatory response of the central nervous system and then participate in the formation of seizures. Glutamate activates astrocytes or microglia expressing NOD-like receptor thermal protein domain associated protein 3 (NLPR-3) and cysteinyl aspartate specific protease 1 (caspase 1), releases substances such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), participates in the inflammatory response and seizure formation of the central nervous system, and activates other Cx43-based hemichannels, which in turn form a wide calcium influx to form calcium waves

Fig. 3

The expression of Cx43 is regulated by the canonical Wnt/β-catenin pathway. This figure showed the expression of Cx43 is regulated by the canonical Wnt/β-catenin pathway. The expression of Cx43 is regulated by the canonical Wnt/β-catenin pathway. In the "OFF" state of the canonical Wnt/β-catenin pathway (lack of Wnt), β-catenin in the cytoplasm is selectively degraded by two multistructural domain scaffold protein axis inhibitor proteins (Axin) and Adenomatous Polyposis Coli gene protein (APC), which are selectively degraded by glycogen synthase kinase-3 (GSK3) and casein kinase 1 (CK1) to promote the amino-terminal phosphorylation of β-catenin. Phosphorylated β-catenin is recognized by the β-transducin repeat-containing protein (β-Trcp), which in turn is degraded. In the "ON" state of the Wnt/β-catenin pathway (presence of Wnt), Wnt forms a trimer with Frizzled (FZD) and Lipoprotein Receptor-related Protein 5 or 6 (LRP5/6). This trimer stabilizes β-catenin by aggregating much Dishevelled (DVL) and Axin in the intracellular region of FZD and LRP5/6, which inhibits phosphorylation of β-catenin. Elevated levels of β-catenin promoted the interaction of the β-linked protein with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors, which activated the expression of the Cx43 gene

Fig. 4

The epileptogenic mechanism of Panx1. This figure showed the epileptogenic mechanism of Panx1. Panx1-based hemichannels are involved in epileptic seizures. After the body is stimulated, according to the above mechanism, astrocytes produce a large amount of the glial transmitter glutamate, which can activate astrocytes’ N-methyl-D-aspartate receptor (NMDAR) to generate SRC to activate Panx1-based hemichannels, and calcium ions pass through this channel. The flow participates in the formation of calcium ion waves and releases adenosine triphosphate (ATP) through this channel. The released ATP can activate other NMDARs again and activate P2X7R to generate SRC, and the subsequent mechanism is the same as that of NMDAR. In addition, a large influx of calcium in astrocytes can act on P2X7R to generate protein kinase C (PKC), which inhibits the effect of muscarinic receptor 1 (M1), thereby inhibiting the effect of Panx1-based hemichannels and inhibiting epileptic seizures