Calcium tsunamis: do astrocytes transmit cell death messages via gap junctions during ischemia?

10.1038/2147 ◽  
1998 ◽  
Vol 1 (6) ◽  
pp. 431-432 ◽  
Author(s):  
Samantha L. Budd ◽  
Stuart A. Lipton
Keyword(s):  
Cell Death ◽  
Gap Junctions

scholarly journals Mechanisms Underlying Connexin Hemichannel Activation in Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3503
Author(s):  
Raf Van Campenhout ◽  
Ana Rita Gomes ◽  
Timo W.M. De Groof ◽  
Serge Muyldermans ◽  
Nick Devoogdt ◽  
...  
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Connexin Hemichannel ◽  
Extracellular Environment ◽  
Connexin Hemichannels

Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the “good guys” by controlling homeostasis, connexin hemichannels are considered as the “bad guys”, as their activation is associated with the onset and dissemination of disease. Open connexin hemichannels indeed mediate the transport of messengers between the cytosol and extracellular environment and, by doing so, fuel inflammation and cell death in a plethora of diseases. The present mini-review discusses the mechanisms involved in the activation of connexin hemichannels during pathology.

scholarly journals Gap Junctions Mediate Bystander Cell Death in Developing Retina

2003 ◽  
Vol 23 (16) ◽  
pp. 6413-6422 ◽  
Author(s):  
Karen Cusato ◽  
Alejandra Bosco ◽  
Renato Rozental ◽  
Cinthya A. Guimarães ◽  
Benjamin E. Reese ◽  
...  
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Bystander Cell ◽  
Bystander Cell Death

Gap junctions and the propagation of cell survival and cell death signals

APOPTOSIS ◽  
2005 ◽  
Vol 10 (3) ◽  
pp. 459-469 ◽  
Author(s):  
D. V. Krysko ◽  
L. Leybaert ◽  
P. Vandenabeele ◽  
K. D’Herde
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Cell Survival ◽  
Death Signals

scholarly journals The role of gap junctions in cell death and neuromodulation in the retina

2021 ◽  
Vol 16 (10) ◽  
pp. 1911
Author(s):  
Tamás Kovács-Öller ◽  
Gergely Szarka ◽  
Márton Balogh ◽  
ÁdámJ Tengölics ◽  
Alma Ganczer ◽  
...  
Keyword(s):  
Cell Death ◽  
Gap Junctions

scholarly journals Ischemia-Induced Brain Damage Depends on Specific Gap-Junctional Coupling

2002 ◽  
Vol 22 (4) ◽  
pp. 453-462 ◽  
Author(s):  
Marina V. Frantseva ◽  
Larisa Kokarovtseva ◽  
Jose L. Perez Velazquez
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Brain Damage ◽  
Connexin 43 ◽  
Cell Injury ◽  
Hippocampal Slices ◽  
Hypoglycemic Episode ◽  
Gap Junctional Communication ◽  
Junctional Communication ◽  
Gap Junctional

Ischemic brain injury results in neuronal loss and associated neurologic deficits. Although there is some evidence that intercellular communication via gap junctions can spread oxidative cell injury, the possible role of gap-junctional communication in ischemia-induced cell death is the object of debate. Because gap junctions directly connect the cytoplasms of coupled cells, they offer a way to propagate stress signals from cell to cell. The authors investigated the contribution of gap-junctional communication to cell death using an in vitro ischemia model, which was reproduced by submersion of organotypic hippocampal slices into glucose-free deoxygenated medium. The gap-junctional blocker carbenoxolone significantly decreased the spread of cell death, as measured by propidium iodide staining, over a 48-hour period after the ischemic episode. Carbenoxolone ameliorated the hypoxia-induced impairment of the intrinsic neuronal electrophysiologic characteristics, as measured by whole-cell patch clamp recordings. To determine whether specific connexins were involved in the spread of postischemic cell death, the authors partially reduced the synthesis of specific connexins using antisense oligodeoxynucleotides. Simultaneous knockdown of two connexins localized mostly in neurons, connexins 32 and 26, resulted in significant neuroprotection 48 hours after the hypoxic– hypoglycemic episode. Similarly, partial reduction of the predominant glial connexin 43 significantly decreased cell death. These results indicate that gap-junctional communication contributes to the propagation of hypoxic injury and that specific gap junctions could be a novel target to reduce brain damage.

scholarly journals Neuronal Gap Junctions Are Required for NMDA Receptor–Mediated Excitotoxicity: Implications in Ischemic Stroke

2010 ◽  
Vol 104 (6) ◽  
pp. 3551-3556 ◽  
Author(s):  
Yongfu Wang ◽  
Janna V. Denisova ◽  
Ki Sung Kang ◽  
Joseph D. Fontes ◽  
Bao Ting Zhu ◽  
...  
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Neuronal Death ◽  
Critical Role ◽  
Intraperitoneal Administration ◽  
Wild Type ◽  
Western Blots ◽  
Connexin 36 ◽  
Fluoro Jade B ◽  
Junction Protein

N-methyl-d-aspartate receptors (NMDARs) play an important role in cell survival versus cell death decisions during neuronal development, ischemia, trauma, and epilepsy. Coupling of neurons by electrical synapses (gap junctions) is high or increases in neuronal networks during all these conditions. In the developing CNS, neuronal gap junctions are critical for two different types of NMDAR-dependent cell death. However, whether neuronal gap junctions play a role in NMDAR-dependent neuronal death in the mature CNS was not known. Using Fluoro-Jade B staining, we show that a single intraperitoneal administration of NMDA (100 mg/kg) to adult wild-type mice induces neurodegeneration in three forebrain regions, including rostral dentate gyrus. However, the NMDAR-mediated neuronal death is prevented by pharmacological blockade of neuronal gap junctions (with mefloquine, 30 mg/kg) and does not occur in mice lacking neuronal gap junction protein, connexin 36. Using Western blots, electrophysiology, calcium imaging, and gas chromatography–mass spectrometry in wild-type and connexin 36 knockout mice, we show that the reduced level of neuronal death in knockout animals is not caused by the reduced expression of NMDARs, activity of NMDARs, or permeability of the blood–brain barrier to NMDA. In wild-type animals, this neuronal death is not caused by upregulation of connexin 36 by NMDA. Finally, pharmacological and genetic inactivation of neuronal gap junctions in mice also dramatically reduces neuronal death caused by photothrombotic focal cerebral ischemia. The results indicate that neuronal gap junctions are required for NMDAR-dependent excitotoxicity and play a critical role in ischemic neuronal death.

Efficient Delivery of Antiapoptotic Signals from Marrow Stromal Cells to Acute Lymphoblastic Leukemia Cells Is Associated with Differential Expression of Genes Related to the Membrane and to Regulation of Apoptosis and Is Dependent in Part on Gap Junction Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5066-5066
Author(s):  
Craig A. Mullen ◽  
Sana Usmani ◽  
Leti Nunez ◽  
Olena Tkachenko
Keyword(s):  
Cell Death ◽  
Gap Junctions ◽  
Gap Junction ◽  
Stromal Cells ◽  
Connexin 43 ◽  
Stromal Cell ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Efficient Delivery ◽  
Cell Support

Abstract Nonmalignant marrow stroma provides a favorable microenvironment for leukemia cell survival. The mechanisms of support are not well understood. Some studies have identified roles for some stromal derived molecules including some growth factors (EGF, FGF, PDGF), adhesion molecules (VCAM, selectins, osteopontins, integrins, fibronectin), cytokines (IL3, IL6, IL7) and others (KITLG, ANGPT1, CXCL12, LGALS3). It is clearly a multifactorial mechanism. We have developed a simple but powerful experimental system of human marrow derived stromal cells co-cultured with primary human high risk ALL cells that allows us to study the molecular mechanisms. Efficient delivery of the antiapoptotic signals requires leukemia cell contact with living, metabolically active stromal cells. Figure 1 shows several conditions in which stromal cell support for ALL is abrogated: (a) when ALL contact with stroma is prevented by a transwell membrane that allows free flow of extracellular medium; (b) after formalin fixation of stromal cells and their matrix; (c) when live stromal cell protein synthesis is prevented by pretreatment of stromal cells with G418 at nonlethal concentrations; (d) when live stromal cell RNA transcription is impaired by pretreatment with triptolide. Efficient delivery of antiapoptotic signals to leukemia cells is associated with differential of genes related to the membrane and extracellular region and to regulation of cell death. We performed we performed RNASeq studies of gene expression in stromal cells and ALL cells. We made comparisons (a) between supporting cells that could (n=17) and could not (n=7) provide antiapoptotic support to ALL, and (b) between ALL cells that were (n=3) and were not (n=3) supported by stromal cells. We identified 409 genes differentially expressed in stromal cells that prevent ALL apoptosis including genes known to play roles in cell surface interactions, cell matrix interactions, growth factor binding and regulation of cell death (Table 1). We identified 458 genes upregulated in ALL cells following contact with stromal cells including genes related to interactions with the extracellular environment, purine metabolism and regulation of apoptosis (Table 2). We identified 494 genes upregulated in stromal cells following contact with ALL related to extracellular interactions, regulation of oxidation, regulation of daunorubicin, regulation of NADP and ethanol metabolism, interferon signaling and regulation of cell proliferation (Table 3). Based on these discoveries we hypothesized that important mechanisms of stromal cell support of ALL might involve direct intercellular exchange of small molecules related to energy metabolism, nucleic metabolism, and messengers regulating cell proliferation and cell apoptosis. Possible mechanisms could include gap junctions, nanotubules or exosomes. The predominant gap junction in human cells is connexin 43 (GJA1). We found that GJA1 is constitutively expressed at high levels by stromal cells, and that GJA1 expression is increased ten-fold in ALL cells upon contact with stromal cells. Rapid bidirectional exchange of intracellular molecules occurs between stromal cells and ALL. We loaded stromal cells with fluorescent calcien AM which once inside a cell cannot diffuse through the membrane but can pass through gap junctions. We cocultured ALL cells with labelled stromal for 16 hr. We observed calcien in ALL cells in physical contact with stroma, but not in ALL cells separated from labelled stroma by a transwell. When leukemia cells were labeled with calcien we saw transfer of calcien to stroma in contact with ALL but not when separated by a transwell. Interference with gap junction function increases ALL cell death. GAP27 is an 11-amino acid peptide that specifically interferes with GJA1/connexin 43 gap junctions. Figure 2 shows substantial reduction of ALL survival in cocultures containing 1 mM GAP27 peptide. We observed similar results with use of 75 micromolar carbenoxolone, an FDA approved drug that impairs gap junction function. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gap junctions and hemichannels: communicating cell death in neurodevelopment and disease

2017 ◽  
Vol 18 (S1) ◽  
Author(s):  
Andrei B. Belousov ◽  
Joseph D. Fontes ◽  
Moises Freitas-Andrade ◽  
Christian C. Naus
Keyword(s):  
Cell Death ◽  
Gap Junctions
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