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Review
. 2020 Mar 31;9(4):846.
doi: 10.3390/cells9040846.

Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection

Oscar F Sánchez  1 , Andrea V Rodríguez  1 , José M Velasco-España  1 , Laura C Murillo  1 , Jhon-Jairo Sutachan  1 , Sonia-Luz Albarracin  1
Affiliations
Review

Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection

Oscar F Sánchez et al. Cells. .

Abstract

Gap junction (GJ) channels and their connexins (Cxs) are complex proteins that have essential functions in cell communication processes in the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes, and microglial cells express an extraordinary repertory of Cxs that are important for cell to cell communication and diffusion of metabolites, ions, neurotransmitters, and gliotransmitters. GJs and Cxs not only contribute to the normal function of the CNS but also the pathological progress of several diseases, such as cancer and neurodegenerative diseases. Besides, they have important roles in mediating neuroprotection by internal or external molecules. However, regulation of Cx expression by epigenetic mechanisms has not been fully elucidated. In this review, we provide an overview of the known mechanisms that regulate the expression of the most abundant Cxs in the central nervous system, Cx30, Cx36, and Cx43, and their role in brain cancer, CNS disorders, and neuroprotection. Initially, we focus on describing the Cx gene structure and how this is regulated by epigenetic mechanisms. Then, the posttranslational modifications that mediate the activity and stability of Cxs are reviewed. Finally, the role of GJs and Cxs in glioblastoma, Alzheimer's, Parkinson's, and Huntington's diseases, and neuroprotection are analyzed with the aim of shedding light in the possibility of using Cx regulators as potential therapeutic molecules.

Keywords: astrocytes; connexins; epigenetics; gap junctions; microglia; neurodegenerative diseases; neurons; neuroprotection.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the distribution of Cxs in the CNS. Cx30 and Cx43 are mainly present in astrocytes; while Cx36 is mainly expressed in neurons.
Figure 2
Figure 2
Schematic representation of the genomic structure of (A) GJB6 (Cx30) on chromosome 13; in the human brain it has been found that GJB6 has only the non-coding exons 3 and 5 and the coding exon 6. (B) GJD2 (Cx36) on chromosome 15, and (C) GJA1 (Cx43) on chromosome 6. Each box represents an exon, and solid red boxes represent the coding regions.
Figure 3
Figure 3
Regulatory epigenetic processes on Cx expression. Histone acetylation, DNA and histone methylation, and microRNAs (miRNA) are presented as the main studied epigenetic controls over Cxs gene regulation. Gene expression is correlated with histone acetylation, low DNA methylation in the promoter region, while gene repression correlates with high DNA methylation in the promoter region and low histone acetylation levels. Histone methylation control on gene expression is residue-specific and also depends on the grade of methylation of the residue. Lysine can be mono-, di- or tri-methylated. KATs: lysine acetyltransferases; HDACs: histone deacetylases; TET1: Tet-Eleven Translocation 1 enzyme, main DNA demethylases in mammals; DNMTs: DNA methyltransferases; HDMs: histone demethylases; KMTs: lysine methyltransferases.
Figure 4
Figure 4
Schematic representation of Cx43 embedded in a cell membrane. Main PTMs present in Cx43 CT are listed. E1 and E2 are external loops, CL is the cytoplasmic loop, and M1 to M4 are the transmembrane domains.
Figure 5
Figure 5
Schematic representation of main perturbations in the expression of Cx30, Cx36, and Cx43 in neurons, astrocytes, and microglia for (A) AD, (B) PD, and (C) HD. Common features are observed across the different neurodegenerative disorders such as reactive astrocytes, active microglia, the release of pro-inflammatory molecules (e.g., TNF-α and IL-1 β), loss of glutamate and K+ buffering capacity, and generation of ROS. Briefly, in AD (A) mutations in the APP gene leads to the accumulation of Aβ plaques, which is associated with increased levels of Cx43 and chronical activation of Cx43 HCs. In PD (B), α-synuclein enhances the opening of Cx43 HCs, leading to high intracellular Ca2+ levels along with the activation of cytokines. In HD (C), abnormally long polyglutamine in HTT protein causes mitochondrial fragmentation, which has been mainly associated with increased Cx43 GJs.
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