Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue

Contreras, Jorge E.; Sánchez, Helmuth A.; Véliz, Loreto P.; Bukauskas, Feliksas F.; Bennett, Michael V. L.; Sáez, Juan C.

doi:10.1016/j.brainresrev.2004.08.002

Cited by 220 publications

(194 citation statements)

References 160 publications

(238 reference statements)

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“…Further, glutamate may leave the astrocytes through hemichannels, which can be opened by lowering of extracellular Ca 2 þ and acidosis or even through P2X 7 receptors, activated by excessively high extracellular ATP; all these do happen during ischaemia. 24 Second, astrocytes may spread the death signals through the brain parenchyma via gap junctions 25 and/ or participate in developing spreading depression, which determine the infarction progress through the penumbra.…”

Section: Glia and Neuropathology: General Perspectivesmentioning

confidence: 99%

“…Indeed, it has been recently reported that Cx hemichannels, which are normally closed became open under experimental ischaemia induced by glucose and oxygen deprivation. 24 Up-to-now, a number of factors may account for the above apparent contradictions. 44 For instance, experimental studies vary considerably with regard to the systems employed and the way used to block hemi-or full-Cx channel-mediated communication.…”

Section: Intercellular Communication In Glia and Neuroprotectionmentioning

confidence: 99%

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Glia: the fulcrum of brain diseases

et al. 2007

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Neuroglia represented by astrocytes, oligodendrocytes and microglial cells provide for numerous vital functions. Glial cells shape the micro-architecture of the brain matter; they are involved in information transfer by virtue of numerous plasmalemmal receptors and channels; they receive synaptic inputs; they are able to release 'glio'transmitters and produce long-range information exchange; finally they act as pluripotent neural precursors and some of them can even act as stem cells, which provide for adult neurogenesis. Recent advances in gliology emphasised the role of glia in the progression and handling of the insults to the nervous system. The brain pathology, is, to a very great extent, a pathology of glia, which, when falling to function properly, determines the degree of neuronal death, the outcome and the scale of neurological deficit. Glial cells are central in providing for brain homeostasis. As a result glia appears as a brain warden, and as such it is intrinsically endowed with two opposite features: it protects the nervous tissue as long as it can, but it also can rapidly assume the guise of a natural killer, trying to eliminate and seal the damaged area, to save the whole at the expense of the part. The sudden emergence of an intellect, and therefore a human being, which materialised only around a million years ago, remains the main mystery for our self-understanding. Similarly, we still do not know by which steps or transitions the human intellect emerged from the animal kingdom and where the fundamental difference between a man and an animal lies. According to the neuronal doctrine, which governs modern neuroscience since the beginning of the twentieth century, 1,2 the neurone is regarded as a basic information processing unit consisting of dendrites and axons with a unidirectional flow of information from the receiving dendrites via the integrating cell body to the terminal branches of the axon. Neuronal networks, connected through synaptic contacts, are generally considered as the substrate of our intellect.The number and size of neural cells increase with the size of the body and of the brain of mammals. This increasing quantity eventually has caused the generation of a new quality, the intellect. Rather amazingly, however, there is a relatively little difference in the morphology and physiology of neurones between humans and beasts; similarly the density of synaptic contacts in the brains of rodents and humans is more or less constant at around 1100-1300 millions/mm 3 . 3 On the contrary, evolution of the nervous system resulted in great changes in the second type of neural cells, the neuroglia. 4 Indeed, phylogenetic advance in brain complexity and capabilities coincided with a remarkable increase in the number of glial cells: in the rodent cortex the glial to neurone ratio is about 0.3 : 1, whereas in humans the same ratio is several times higher being B1.65:1, 5 while the total number of glial cells in the human brain is B10 (or even more) times larger than in lesser mammals. Astrocytes ...

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Section: Glia and Neuropathology: General Perspectivesmentioning

confidence: 99%

Section: Intercellular Communication In Glia and Neuroprotectionmentioning

confidence: 99%

Glia: the fulcrum of brain diseases

et al. 2007

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“…The gap junction "bystander effect" occurs when a dying cell delivers a cellular apoptotic signal such as high Ca +2 or ATP to an adjacent cell through open gap junctions which, in turn, causes spread of the death signal [4]. The process is well-documented in brain ischemia [10][11][12]. Retinal ischemia induces retinal cell death in a caspase-dependent manner [13].…”

Section: Introductionmentioning

confidence: 99%

Protection of retinal cells from ischemia by a novel gap junction inhibitor

Das¹,

Lin²,

Jena³

et al. 2008

Biochemical and Biophysical Research Communications

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Retinal cells which become ischemic will pass apoptotic signal to adjacent cells, resulting in the spread of damage. This occurs through open gap junctions. A class of novel drugs, based on primaquine (PQ), was tested for binding to connexin 43 using simulated docking studies. A novel drug has been synthesized and tested for inhibition of gap junction activity using R28 neuro-retinal cells in culture. Four drugs were initially compared to mefloquine, a known gap junction inhibitor. The drug with optimal inhibitory activity, PQ1, was tested for inhibition and was found to inhibit dye transfer by 70% at 10 μM. Retinal ischemia was produced in R28 cells using cobalt chloride as a chemical agent. This resulted in activation of caspase-3 which was prevented by the PQ1 gap junction inhibitor. Results demonstrate that novel gap junction inhibitors may provide a means to prevent retinal damage during ischemia.

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“…During ischemia or stroke, cell death signals may pass through gap junction channels to adjacent cells (Velaquez et al, 2003;Contreras et al, 2004;Thompson et al, 2006). This gap junction "Bystander effect" accounts for cell death (Farahani et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

Lin

Shanks

Prakash

et al. 2007

Experimental Eye Research

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Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C γ (PKCγ) acts as a primary oxidative stress sensor in the lens. PKCγ has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCγ proteins causes a failure of the PKCγ oxidative stress response (Lin and Takemoto (2005) (100 μM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCγ mutations. The presence of 18α-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H 2 O 2 -induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCγ C1B mutations on endogenous PKCγ which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to extent of loss of C1B structure. Mutations in the C1B domain of PKCγ result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cellto-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCγ.

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Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue

Cited by 220 publications

References 160 publications

Glia: the fulcrum of brain diseases

Glia: the fulcrum of brain diseases

Protection of retinal cells from ischemia by a novel gap junction inhibitor

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

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