Abstract
Gap junctions (GJs) are expressed in most cell types of the nervous system, including neuronal stem cells, neurons, astrocytes, oligodendrocytes, cells of the blood brain barrier (endothelial cells and astrocytes) and under inflammatory conditions in microglia/macrophages. GJs connect cells by the docking of two hemichannels, one from each cell with each hemichannel being formed by 6 proteins named connexins (Cx). Unapposed hemichannels (uHC) also can be open on the surface of the cells allowing the release of different intracellular factors to the extracellular space. GJs provide a mechanism of cell-to-cell communication between adjacent cells that enables the direct exchange of intracellular messengers, such as calcium, nucleotides, IP3, and diverse metabolites, as well as electrical signals that ultimately coordinate tissue homeostasis, proliferation, differentiation, metabolism, cell survival and death. Despite their essential functions in physiological conditions, relatively little is known about the role of GJs and uHC in human diseases, especially within the nervous system. The focus of this review is to summarize recent findings related to the role of GJs and uHC in physiologic and pathologic conditions of the central nervous system.
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Acknowledgments
We apologize to the authors and groups whose work we did not cite due to limitations on the numbers of references. This work was supported by the National Institute of Mental Health grants (MH076679 and MH096625 to E.A.E. and MH075679 and MH083497 to J.W.B.) and by the National Institute of Neurological Disorders and Stroke (NS072238 to FFB, and NS55363 to M.V.L.B, who is the Sylvia and Robert S. Olnick Professor of Neuroscience). We thank the National Multiple Sclerosis Society Grant RG-1001-K-11 and CSR was the Wollowick Family Foundation Professor for Multiple Sclerosis Research (to Dr. Cedric Raine). We thank the NIH Centers for AIDS Research Grant (CFAR) AI-051519, Anillo ATC-71 (JCS) and Centro interdisciplinario de Neurociencias P09-022-F (to JCS) and a CFAR pilot project at the Albert Einstein College of Medicine.
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Figure 1
Human astrocytes infected with HIVJR-CSF induce apoptosis and alterations in glutamate metabolism through GJ. (A) HIV infection of astrocytes for 21 days induces apoptosis of the surrounding neurons as determined by TUNEL staining. This apoptosis induced by a few infected astrocytes was GJ dependent, because the addition of AGA (32 μM) reduced bystander neuronal apoptosis to control levels. (B) Analyses of glutamate release to the media indicated that HIV-infection increased levels of extracellular glutamate, and that concurrent addition of AGA further enhanced glutamate release, suggesting that extracellular glutamate is not directly responsible for neuronal apoptosis, because when GJ are blocked cells are protected from apoptosis. * Represents significant difference as compared to control conditions (p < 0.005; n = 4). # represents significant differences between HIV infection as compared to HIV infection plus AGA (p < 0.005; n = 3). (PPT 86 kb)
Figure 2
Gap junction channels control release of inflammatory cytokines in rat microglia. Rat microglia cultures treated with LPS (1 μg/ml) and IFN-γ (10 ng/ml), a condition that induces functional GJ coupling in these cells (Eugenin et al. 2001. 2003, 2007), trigger strong secretion of TNF-α, IL1-β and IL-6 (parallel lines bars) as compared to control conditions (white bars). Addition of AGA (32 μM) to the LPS and IFN-γ treated microglia, to block GJ channels, resulted in significant decrease of secretion of TNF-α and IL1-β, but not IL-6 (cross line bars), suggesting that functional GJ are essential to enhance secretion of some inflammatory factors. * Represents significant difference as compared to control conditions (white bars, p < 0.0005; n = 6) and # represents significant differences between LPS and IFN-γ treated microglia as compared to LPS+ IFN-γ and AGA treated microglia (p < 0.007; n = 5). (PPT 103 kb)
Figure 3
HIV-infected PBMC (A) and microglia (B) in HIV encephalitic human tissue express higher levels of Cx43 as compared to uninfected PBMC or uninfected brain tissue, respectively. HIVADA-infected PBMC treated with MCP-1/CCL2 (100 ng/ml) were analyzed by phase contrast (small insert) and confocal microscopy (A) for Cx43 staining. After infection, PBMCs expressed higher levels of Cx43 as compared to the undetectable levels in uninfected cells. Inset shows the phase picture of the cells. (B) Human brain tissue was analyzed by confocal microscopy for Cx43 (B), CD68 (small insert, microglia/macrophages) and phase contrast (small insert). Normal tissue did not show any staining for Cx43 in CD68 positive cells (data not shown). However brain tissue sections obtained from HIV-infected individuals with CNS compromise (encephalitis, HIVE), expressed Cx43 in microglia/macrophages (Micro) in close contact with neurons (Neu). Arrows, indicate areas of potential GJ areas between microglia and neurons. Also lines were drawn to distinguish the cell limit of microglia and neurons. Bar: 70 μm (PBMCs staining) and 180 μm (tissue staining). (PPT 1159 kb)
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Eugenin, E.A., Basilio, D., Sáez, J.C. et al. The Role of Gap Junction Channels During Physiologic and Pathologic Conditions of the Human Central Nervous System. J Neuroimmune Pharmacol 7, 499–518 (2012). https://doi.org/10.1007/s11481-012-9352-5
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DOI: https://doi.org/10.1007/s11481-012-9352-5