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Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction.
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PMID:  22864302     Owner:  NLM     Status:  MEDLINE    
Loss of energy supply to neurons during stroke induces a rapid loss of membrane potential that is called the anoxic depolarization. Anoxic depolarizations result in tremendous physiological stress on the neurons because of the dysregulation of ionic fluxes and the loss of ATP to drive ion pumps that maintain electrochemical gradients. In this review, we present an overview of some of the ionotropic receptors and ion channels that are thought to contribute to the anoxic depolarization of neurons and subsequently, to cell death. The ionotropic receptors for glutamate and ATP that function as ligand-gated cation channels are critical in the death and dysfunction of neurons. Interestingly, two of these receptors (P2X7 and NMDAR) have been shown to couple to the pannexin-1 (Panx1) ion channel. We also discuss the important roles of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in responses to ischemia. The central challenge that emerges from our current understanding of the anoxic depolarization is the need to elucidate the mechanistic and temporal interrelations of these ion channels to fully appreciate their impact on neurons during stroke.
Nicholas L Weilinger; Valentyna Maslieieva; Jennifer Bialecki; Sarup S Sridharan; Peter L Tang; Roger J Thompson
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Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2012-08-06
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  34     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-11-18     Revised Date:  2014-10-15    
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Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  United States    
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Languages:  eng     Pagination:  39-48     Citation Subset:  IM    
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MeSH Terms
Brain / blood supply*,  metabolism,  pathology*
Brain Ischemia / etiology,  metabolism*,  pathology*
Cell Death
Connexins / metabolism
Ion Channels / metabolism*
Neurons / metabolism,  pathology*
Receptors, Purinergic / metabolism
Stroke / complications,  metabolism,  pathology
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Connexins; 0/Ion Channels; 0/Receptors, Purinergic

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Journal ID (nlm-ta): Acta Pharmacol Sin
Journal ID (iso-abbrev): Acta Pharmacol. Sin
ISSN: 1671-4083
ISSN: 1745-7254
Publisher: Nature Publishing Group
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Copyright © 2013 CPS and SIMM
Received Day: 06 Month: 04 Year: 2012
Accepted Day: 08 Month: 06 Year: 2012
Print publication date: Month: 01 Year: 2013
Electronic publication date: Day: 06 Month: 08 Year: 2012
Volume: 34 Issue: 1
First Page: 39 Last Page: 48
PubMed Id: 22864302
ID: 4086487
Publisher Item Identifier: aps201295
DOI: 10.1038/aps.2012.95

Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction
Nicholas L Weilinger1
Valentyna Maslieieva1
Jennifer Bialecki1
Sarup S Sridharan1
Peter L Tang1
Roger J Thompson1*
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada


Ischemia is a consequence of the loss of blood flow to tissues or organs. The principle result is a restriction in the delivery of the energy substrates, oxygen and glucose, to cells in the affected area. It is important to note that ischemia also causes several other detrimental stimuli, including acidosis (hypercapnia) and cessation of blood flow that is likely important for regulation of vascular tone. In the laboratory in vitro setting, ischemia is typically modelled as its constituent components, anoxia, hypoglycemia, O2/glucose deprivation (OGD), or acidification; the primary reason being that it makes dissecting the complex molecular mechanisms of cellular death and dysfunction more tractable.

In the brain, ischemia occurs as a consequence of stroke or cardiac arrest. One of the early, major effects of ischemia on neurons is the appearance of a large inward current that is carried by cation influx, and is responsible for the anoxic depolarization (AD). The AD can be measured in vitro and in vivo, and consists of a rapid loss of membrane potential, unregulated calcium influx, loss of the neuron's ability to produce ATP and characteristic dendritic and axonal beading1,2,3. The focus of this review is to summarize the roles of some of these cation channels and their contribution to the AD and its inward currents. Specifically, glutamate-gated ion channels, ATP-binding purinergic receptors, pannexin1 channels, and other channel mediators (TRP and ASIC) will be discussed. One central challenge of the field is to reconcile the temporal and mechanistic relationships of these various ion channels, so that effective therapeutics for neuroprotection and enhanced recovery can be developed.

Glutamate-gated ionotropic receptors and ischemia

The longstanding paradigm of ischemia-induced cell death has been that uncontrolled opening of ionotropic glutamate receptors induces excitotoxcity, and that this death of neurons by over-activation is responsible for the neurological deficits following stroke. In response to increased release of presynaptic glutamate4 or reversal of uptake mechanisms in astrocytes5, there is an accumulation of extracellular glutamate and subsequent over-stimulation of post-synaptic N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptors that mediate cationic inward currents (Figure 1).

NMDA receptors (NMDARs) are cation permeable ligand-gated ion channels that have prominent roles in physiological synaptic functions. Activation of NMDARs contributes to the plasticity of synaptic strength, and by extension, the sub-cellular mechanisms underlying some forms of learning and memory. NMDARs are unique from other ligand-gated ion channels insofar as they are “coincidence detectors” not only do they require glutamate and glycine (or D-serine) as co-agonists to induce channel opening6,7,8,9, but they also need a concurrent membrane depolarization to alleviate a voltage-sensitive Mg2+ block in the pore10. NMDAR opening allows influx of Na+ (which will contribute to membrane depolarization), and more importantly Ca2+ influx, which mediates subsequent physiological as well as pathophysiological effects.

NMDARs are heterotetramers comprised of GluN1 (ubiquitously expressed), GluN2(A-D) and GluN3(A-B) subunits; the resultant receptor composition will govern Ca2+ permeability, and the affinity of Mg2+ for the pore and glutamate and glycine at their ligand-binding sites11,12,13,14. In that light, NMDAR contribution to glutamate excitotoxicity is thought to be directly dependent on subunit expression. For example, GluN3A-containing NMDARs are impermeable to Ca2+, have decreased Mg2+ block11,15, and have been reported to be neuroprotective during ischemia16.

Ca2+ conductance through NMDARs can promote both apoptotic and necrotic pathways. One means through which NMDARs achieve this is via direct activation of neuronal nitric oxide synthase (nNOS; Figure 1), which is anchored in a complex with NMDARs via a PSD-95 binding domain on the C-terminus of GluN2 subunits17. Ca2+ currents through NMDARs transiently activate nNOS to produce nitric oxide (NO), which subsequently activates a plethora of cascades. NO production directly induces ATP depletion by inhibiting mitochondrial cytochrome oxidase, by generating reactive oxygen species (ROS), and enhancing presynaptic glutamate release through retrograde signalling18,19,20. Concurrent increases in intracellular Ca2+ and ROS may also lead to mitochondrial permeability transition (and thus cytochrome c release), as well as activating caspases and calpains, which trigger apoptosis and necrosis21,22 (Figure 1).

It is by no means a stretch to conclude that activation of NMDARs plays a crucial role in perpetuating cell death pathways, and yet clinical development of NMDAR-targeting pharmacological interventions was ineffective in treating or minimizing stroke damage in patients. In spite of the considerable promise of neuroprotection of NMDAR block from in vitro and in vivo animal studies, clinical trials on all NMDAR antagonists were halted due to lack of efficacy23,24. NMDARs are not, however, the sole conduit for Ca2+ entry during ischemia (see below), and therefore targeting Ca2+-signalling cascades may be a more strategic approach to blocking neuronal death. Emerging evidence suggests key differences between neuronal responses to activation of synaptic or extrasynaptic NMDARs. The more-abundant, extrasynaptic NMDARs promote cell death25, while synaptic NMDARs might in fact be neuroprotective through Ca2+ dependent activation of CREB (for recent review, see26).

In addition to NMDARs, AMPA receptors are also proposed to mediate cell death during ischemia27. AMPARs are tetrameric ligand gated ion channels, composed of a combination of GluA1-4 subunits and, unlike NMDARs, are activated solely by glutamate binding. Though historically not considered to be as critical as the NMDAR in perpetuating excitotoxic cell death, AMPARs may also mediate (or initiate) pathological cationic influx. Indeed, early studies on rodent models have shown that administration of AMPAR antagonists can be neuroprotective during ischemia28,29. One key feature that differentiates some AMPARs from NMDARs is the inability of GluA2 containing AMPARs to conduct Ca2+, reducing the possibility of activating Ca2+-mediated neurotoxic cascades directly. However, AMPARs may contribute indirectly to neurotoxic cascades through membrane depolarizations that are sufficient to remove the Mg2+ block of NMDAR and facilitate opening or by recruitment of other Ca2+ influx pathways.

The majority of AMPARs expressed in neocortical and hippocampal pyramidal neurons are GluA2-containing channels30,31,32, a subunit that contains a positively charged arginine (R) in the pore forming domain of the channel, rendering the AMPAR impermeable to Ca2+ ions33. Transgenic expression of a glutamine (Q) in lieu of arginine (R) on GluA2 is permissive of Ca2+ conduction34; prolonged opening of GluA2(Q)-containing AMPARs (and not GluA2(R) receptors), are proposed to play a pivotal role during ischemic cell death34. On the other hand, GluA2-lacking receptors (consisting of GluA1, GluA3, or GluA4) are permeable to divalent Ca2+ and Zn2+35,36, and are strongly implicated in global ischemia/glutamate excitotoxicity in vivo37.

AMPAR trafficking and subunit assembly are dynamic processes under both physiological (for example, in long-term potentiation and depression) and pathophysiological conditions (for review, see38). Regulation of AMPARs has been extensively studied during neurodegenerative conditions, such epilepsy, brain trauma, and ischemia. Notably, surface expression of GluA2-containing AMPARs is downregulated following ischemic insult, with a subsequent increase in AMPAR-mediated Ca2+ influx (by GluA2-lacking AMPARs) following global ischemia39,40. Similar to NMDARs, activation of AMPARs have also been shown to induce NO production via nNOS41, as well as Ca2+-dependent calpain activity in culture42. Contrary to this, AMPA stimulation might promote neuroprotection through CREB and BDNF activity43. Thus, it is clear that GluA2-lacking AMPARs confer a significant role in mediating cell death during glutamate excitotoxicity, which is likely occurring through Ca2+-dependent pathways analogous to those seen in NMDAR overstimulation.

Purinergic receptors

There are two major groups of purinergic receptors, adenosine-gated P1 and P2 that are opened by uridine tri and di-phosphates as well as adenosine44,45. The P1 receptors are metabotropic and include the A1 and A3 subtypes, which enhance phospholipase C activity and inhibit adenylyl cyclase, and the A2A and A2B subtypes that enhance production of cAMP. The P2 receptors comprise both the ionotropic P2X, and metabotropic G protein-coupled P2Y receptors. The P2 family are widely expressed in tissues and in diverse cell types, including neurons, astrocytes, microglia and oligodendrocytes in the central nervous system. Both adenosine and adenosine-5′-triphosphate (ATP) can signal in physiological and pathological conditions and whether this is neuroprotective or neurodegenerative depends upon the receptor subtypes involved44,45.

Following the onset of ischemia, the intracellular concentration of ATP decreases46,47, resulting in a dramatic ionic imbalance and subsequent anoxic depolarization-like events48. This is associated with enhanced glutamate (see above) and ATP release into the extracellular milieu49, resulting in activation of P2 receptors. After prolonged activation, P2X7 receptor function can transition from a small, cation permeable channel to one with characteristics of a significantly larger, non-specific pore50,51. Several models for how this occurs have been proposed (reviewed in52), the most recent involving the recruitment of pannexin-1 (Panx1) channels53,54 (reviewed in55; see below).

Disruption of the membrane, as well as apparent activation of Panx1 permits rapid efflux of ATP from the cytosol to the extracellular space. The physiological concentration of ATP is typically high in neurons (millimolar range) — ischemia can induce a rapid increase in extracellular ATP to cytotoxic levels, such that cells (which are uninjured initially) can rapidly succumb to cell death56,57. In addition to release of ATP through Panx1, the purine may also leave neurons and astrocytes by several other mechanisms, including permeation through connexin hemichannel's exocytosis58,59,60,61, and via the ABC transporters/osmolytic transporters that are linked to anion channels62,63. Regardless of the exact mechanism of release, it is clear that excessive ATP can contribute to cell death due to recruitment of a 'death complex' that includes P2X7 receptors and Panx164,65.

There are several studies that demonstrate upregulation of purinergic receptors and neuroprotective effects of antagonizing ATP signalling during ischemia and brain injury (extensively reviewed in66) — for the purpose of this review, we will only mention the most recent studies. Ischemia reportedly elevates expression of several P2 receptors (P2X1, 2, 4, 7, and P2Y4) in dissociated neuronal or organotypic cultures, suggesting that these subunits may be important for pathological responses to ATP during insults67,68,69. In support of this notion, block of P2X7 during focal ischemia reduced infarct size70 and, analogous to neuroprotection, protected optic nerve oligedendrocytes from ischemic damage71.

The non-selective P2 receptor antagonists, PPADS (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate) and suramin decreased infarct size and facilitated functional recovery following animal stroke models72,73,74. Similar effects have been reported in vitro, where inhibition of P2Y1, P2X3, and P2X7 receptors in rat hippocampal slices exposed to OGD significantly attenuated depression of field excitatory postsynaptic potentials (fEPSPs) and anoxic depolarizations75. The same study also demonstrated that downstream activation of the kinases ERK1/2 was involved in synaptic failure and neuronal damage. Interestingly, activation of purinergic receptors by ATP may also be neuroprotective. ATP released during cortical spreading depression was reported to activate P2Y receptors, followed by synthesis of new proteins, which in turn exerted neuroprotective effects, possibly through preconditioning60.

Under normal conditions, adenosine typically inhibits neuronal excitability by attenuating evoked release of glutamate from the presynaptic neuron76,77,78. The effects of adenosine receptor activation, similar to P2X/P2Y receptors, are reported to be both protective and detrimental. For example, inhibition of A2A signalling in a model of focal ischemia is thought to be neuroprotective79, while ischemic brain injury was reduced by activation of A3 receptors80.

Ischemic elevation of extracellular adenosine may be due to increased activity/expression of exonucleotidase, which participates in hydrolysis of ATP to adenosine81,82,83. It is likely therefore, that the release of ATP and adenosine under ischemic conditions is mechanistically and temporally separated49, suggesting that the initial elevations in ATP can activate neurodegenerative mechanisms that may be followed, after conversion of ATP to adenosine by neuroprotective and neurodegenerative roles for the purines. However, this appears to be strongly dependent upon CNS region, animal model and the type of insult, and requires more investigation to elucidate these complex mechanisms80,84,85,86,87,88,89,90,91,92,93,94,95,96.

Pannexin channels

The pannexin family of proteins was first identified by Panchin et al97 over a decade ago by using a degenerate PCR strategy in a search for vertebrate homologs of invertebrate gap junctions (innexins). It is now known that there are three family members (Pannexin-1, -2, and -3) with differential tissue distributions. Northern blot analysis shows that Pannexin-1 (Panx1) mRNA is found in wide variety of tissues, and has high expression levels in the brain and immune cells98. Expression of Panx2 mRNA on the other hand, is restricted to the brain and appears to have an intracellular distribution when modified by S-palmitoylation in neural progenitor cells98,99. Alignment of mRNA and amino acid sequences demonstrate significant similarity between Panx3 and Panx1 with Panx3 being more closely related to Panx1 than Panx2, but the tissue distribution of Panx3 appears to be limited to synovial fibroblasts and osteoblasts98.

The first indications that Panx1 channels were involved in anoxic depolarizations came from our work100 where we showed using acutely isolated hippocampal neurons that OGD activated Panx1 channels. The main implications of this work were that Panx1 channels could be directly activated by ischemia, and the mechanism by which this activation occurred was independent of ligand-gated receptors because blocking NMDA, AMPA and P2X7 receptors failed to alter the large anoxic depolarization's inward currents activated by OGD100. It was later suggested that Panx1 opening in isolated neurons was mediated by the production of NO, and the authors' predicted that this could involve a nitrosylation reaction101. However, the mechanism by which NO acts on Panx1 to mediate channel opening during ischemia has not been identified. One intriguing possibility is that cysteine residues in the C-terminal are involved in activation of Panx1 by NO because mutation of C346 produced constitutively active channels and cell death102.

Is Panx1 activation important for neuronal death during stroke? This question has taken some time to answer considering that the first description of Panx1 activation by ischemia was in 2006. Recently, two groups from Heidelberg, the Monyer and Schwaninger labs collaborated to show that genetic deletion of both Panx1 and Panx2 decreased stroke lesion volumes in mice subjected to permanent middle cerebral artery occlusion103. These results were both exciting and intriguing. The exciting part is, of course, that knockout of pannexin channels contributed to neuroprotection in stroke. The intriguing part lies in the observations that Panx1/2 knockouts appear phenotypically normal (i.e. breed normally and don't have any obvious behavioural abnormalities), and that both channels had to be knocked out to detect significant neuroprotection. Given the wide distribution in Panx1 tissue expression, one might expect a more deleterious effect when not present. This suggests that there may be some developmental compensation for deletion of pannexins. Another possibility, is that there is no normal physiological role for pannexins. This however, seems highly unlikely because data are emerging that Panx1 is involved in ATP release from cells104,105 and is important in regulating proliferation of neuronal stem cells106.

How are pannexins being activated during stroke? Clearly a stroke in the brain is much more complicated than just OGD of isolated neurons. As described above, one of the central consequences of ischemic exposure is the uncontrolled release of the neurotransmitters, glutamate and ATP. In 2008, we described a role for the NMDA receptor in activating Panx1, which contributed to interictal (ie aberrant bursting) in hippocampal pyramidal neurons in acute brain slices107. This work demonstrated that Panx1 can be involved in neuronal plasticity, but also that over-stimulation of NMDA receptors can recruit Panx1, implicating Panx1 channels in excitotoxic neuronal death (Figure 1). It is important to note that direct demonstration of an NMDAR-Panx1 role in excitotoxicity has not yet been shown, but is certainly suggested by the work of Bargiotas et al103 in Panx1/2 knockout mice. Furthermore, the intermediary mechanism(s) that couple NMDARs to Panx1 have not yet been characterized.

Interestingly, the purinergic receptor, P2X7 can directly couple to Panx1, although the mechanistic details, like NMDAR-Panx1, remain unknown. The nature of the role of Panx1 in functioning as the large pore of the P2X receptors is still controversial and has been reviewed elsewhere55 so it will not be the focus here. Regardless of whether or not Panx1 is the “large pore mode” of the P2X7 channel, it is clear from work from several labs that P2X7 receptors can induce opening of Panx1108,109,110,111,112. In J774 cells, this appears to involve the Src family of protein tyronsine kinases (SFKs110). It has also been reported that SFK activity is increased during ischemia, suggesting that in neurons expressing both P2X7 and Panx1, SFKs could play a role in neuronal death113,114. Other studies, however, also suggest that SFKs may have a neuroprotective role following ischemic insult by a mechanism that may involve regulation of ERK and stimulating proliferation of dentage gyrus neuronal cells115,116. The relationship between pannexin channels and purinergic receptors was further demonstrated in the study by Kawamura Jr et al117, who uncovered a significant contribution of Panx1 to neuronal excitability through ATP release.

Mechanisms governing Panx1 activation, other than recruitment by ligand-gated ion channels, have also been proposed. These include truncation of the Panx1 C-terminal by caspases. Chekeni et al64 suggested Panx1 was responsible in part for the release of ATP and UTP during apoptosis, which recruits monocytes and macrophages. In their model, Chekeni et al, propose that Panx1 is targeted for cleavage at the C-terminus by caspase-3 and -7, resulting in channel opening, and consequential purine release. Thus, Panx1 can release “find-me” signals to immune cells during apoptosis. Interestingly, Panx1 was not required for the apoptotic process, but rather seems to act as the pathway for release of death signals118. Panx1 may also be opened by rises in extracellular K+, independently of membrane depolarization and contribute to seizure phenotypes119. Similarly, in a more recent study by Gulbransen et al109, we show that Panx1 is involved in death of neurons in the enteric nervous system (gut) following inflammation models of Crohn's and colitis. The mechanism of neuronal death is however, not clear but appears to involve activation of the inflammasome53.

Transient receptor potential (Melastatin) channels

Transient receptor potential (TRP) channels are a family of tetrameric cation-permeable channels that employ unique mechanisms of activation, spanning mechanosensation (membrane stretch), temperature, and naturally occurring exogenous agonists120,121. These channels are expressed throughout the nervous system, and have been noted to play a critical role in delayed cell death after ischemic insult in the CNS122. The TRP channel family consists of six main subfamilies, and are involved in a whole host of processes (downstream of Ca2+ influx) such as sensation, cell proliferation and fertility123. Two species of TRP channels from the TRPM (Melastatin) super family including TRPM2 and TRPM7, have been reported to contribute to neuronal cell death in the brain124.

Cell death due to TRPM2 and TRPM7 appear to be a consequence of delayed calcium dysregulation following ischemia124 (Figure 1). TRMP2 can be activated by arachidonic acid, reactive oxygen species (ROS), nitric oxide (NO) and adenine 5′-diphosphoribose (ADPR), while TRPM7 is activated by various components involved in stroke such as peroxynitirite, free radicals and change in extracellular pH125. TRPM2 and TRPM7 are permeable to Ca2+ while TRPM2 is also permeable to Na+ and K+126. TRPM7 is also thought to mediate the influx of other divalent metals such as Zn2+ and is also permeable to Mg2+127. Conductance of Zn2+ and Mg2+ by TRPM7 occlude monovalent ions from permeating through the pore122. Unlike TRPM2, which produce a linear current-voltage curve, TRPM7 currents exhibit a large outward rectification124. However, this outward rectification will linearize when divalent cations, such as calcium, are absent from the extracellular space124, which may allow for opening of the channel at resting potentials or under pathophysiological conditions such as ischemia.

TRPM7 was shown by Aarts et al (2003) to mediate a cation current (IOGD) that the authors reported to be lethal to neurons122. This current arises under conditions of OGD and is activated by ROS, which increases Ca2+ uptake by the neuron122 (Figure 1). Furthermore, the use of antiexcitotoxic therapy (AET), with drugs such as MK-801, CNQX and nimodipine, could protect neurons from death if given one hour prior to stroke128. When TRPM7 was knocked down in culture by siRNA, cell death due to anoxia decreased significantly even without the use of AET122. This demonstrates the importance of TRPM7 in in vitro models of toxicity, such that when TRPM7 is inhibited or silenced there is increased neuronal survival during ischemia122. The importance of TRPM7 channels in neuronal death using in vivo stroke rodent models has been shown by either silencing TRPM7 directly or when its activation (among other pathways) was disrupted with use of a PSD-95 interfering peptide129,130. A recent and exciting report shows that disruption of TRPM7/PSD95/neuronal nitric oxide synthase with the NR2B C-terminal mimetic peptide dramatically reduced focal stroke damage in primates129. Taken together, these studies have demonstrated a clear role for TRPM7 in neuronal death caused by OGD.

TRPM2 channels are also strongly implicated in neuronal death through a mechanism that involves a large calcium influx induced by oxidative stress, exogenous hydrogen peroxide (H2O2), or tumor necrosis factor α (TNF-α)131. Zhang et al (2003) activated an isoform of TRPM2 with H2O2 that caused cell death in expression systems132. Consistent with this, when TRPM2 was either pharmacologically inhibited or knocked down by shRNA strategies, there was reduced calcium influx and greater cell survival. An increase in cortical levels of TRPM2 mRNA has also been reported following ischemia, but whether or not this is detrimental to neuronal survival in vivo is unclear133, and it appears that TRPM2 is important for oxidative stress induced cell death. A role for TRPM2 in neuronal death in vivo is clearly the logical next step to confirm the importance of these channels.

Acid sensing ion channels

A critical consequence of ischemia during stroke is acidosis, resulting primarily from lactate production when oxidative phosphorylation fails and neurons switch to glycolysis134. This decrease in pH to values below 6 can be an important cause of cell death135. Although the effects of acidification have been less intensly investigated compared to OGD, recent reports suggest that decreases in tissue pH during ischemia may trigger the opening of acid sensing ion channels (ASICs). The ASICs can facilitate sodium and calcium influx and thereby contribute to ionic dysregulation136,137.

ASICs are ligand-gated ion channels that are part of the epithelial sodium channel family (ENaC) and are activated by low extracellular pH138,139. The recently resolved structure of ASIC1 shows a trimeric channel with each ASIC subunit having two transmembrane domains and a large extracellular loop comprising 350–370 amino acids140,141,142. Expression of ASICs appears limited to the peripheral and central nervous systems of chordates; non-neural cells and other phyla fail to express the channels143. To date, four genes (ASIC1-ASIC4) are known to code for the six different ASIC subunits (ASIC1a, -1b, -2a, -2b, -3, -4)138,139. Four of the ASIC subunits (ASIC1a, 1b, 2a, and 3) can form functional homomeric channels, each having different biophysical properties138,139. Although all ASIC channels conduct Na+ upon activation and exhibit differential sensitivities for pH, only ASIC1a homomeric channels are Ca2+ permeable134,136,137.

Block of ASIC1a contributes to neuroprotection in animal models of stroke136,137,144,145. Cultured cortical neurons subjected to OGD elicit inward currents that could be inhibited by ASIC1a antagonists, amiloride or PcTx venom136. Additionally, exposure of cortical neurons to pH 6.0 in the presence of glutamatergic and voltage-sensitive calcium channel blockers leads to an increase in intracellular Ca2+ that is sensitive to ASIC1a blockers, amiloride or psalmotoxin136. In vivo, occlusion of the middle cerebral artery in knockout mice lacking ASIC1a had smaller infarct sizes compared to control animals136. In addition, it appears that ASICs are not only involved in mediating neurotoxicity during the ischemic event (Figure 1), but that blocking ASIC1a activity up to 5 h post reperfusion significantly reduced infarct volumes144, suggesting an ongoing neurodegeneration due to ASIC1a activation. Thus, ASIC1a opening during ischemia may be a crucial mediator of acidosis-induced neuronal death.

Gao et al demonstrated that there is an ischemia-induced enhancement of ASIC1a activity due to phosphorylation of Ser478 and Ser479, which enhances permeability to cations145. It is well known NMDARs are activated during ischemia (see above)134 and it appears that activation of NMDARs containing the NR2B subunit causes a cascade that recruits Ca2+/calmodulin dependent protein II (CaMKII), which phosphorylates ASIC1a145. Moreover, preventing the increased ischemia-induced permeability of ASIC1a by applying NR2B or CaMKII antagonists leads to decreased intracellular calcium and decreased neuronal death145. In addition to the NMDAR-CaMKII cascade, extracellular spermine and dynorphin appear to mediate ASIC1a channel opening either during, or immediately following ischemia146,147. Taken together, it appears that ischemia-mediated acidosis triggers ASIC1a channel opening that may mediate an alternative, glutamate receptor independent (but NR2b-modulated) calcium influx pathway. Block of ASIC-1a channels during ischemia could, therefore, lead to better functional outcomes in individuals who have suffered stroke.

Concluding remarks

Here we have discussed several key channels thought to be involved in ischemia mediated neuronal damage. One of the interesting themes emerging from the past several decades of work is that the ligand gated cation channels, NMDARs, P2XRs (and others) may couple directly to pannexin-1 channels, which would be important for potentiating the excitotoxic effects of receptor overstimulation. It is important however to remember that several other ion channels are critically involved, including members of the TRP and ASIC families and that both of these can be regulated or modulated by the NMDAR. It remains a challenge of the field to determine the mechanisms of activation of many of these channels and to quantify their temporal relationships during stroke. In particular, separation of the contribution of direct activation of channels by ischemia-induced intermediates versus activation by coupling to ligand-gated channels is critical.

Funding from the Canadian Institutes of Health Research, Alberta Innovates — Health Solutions (AIHS), Heart and Stroke Foundation of Canada, and the Canadian Stroke Network, supports research in the Thompson lab. RJT holds a Scholar award from AIHS and a New Investigator Award from the Heart and Stroke Foundation of Canada. NLW holds an AIHS studentship. SSS was the recipient of a Canadian Stroke Network Summer Studentship.

Zhang S,Boyd J,Delaney K,Murphy TH. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemiaJ NeurosciYear: 2005255333815930381
Winship IR,Murphy TH. In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after strokeJ NeurosciYear: 200828659260618579732
Murphy TH,Li P,Betts K,Liu R. Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spinesJ NeurosciYear: 20082817567218272696
Fleidervish IA,Gebhardt C,Astman N,Gutnick MJ,Heinemann U. Enhanced spontaneous transmitter release is the earliest consequence of neocortical hypoxia that can explain the disruption of normal circuit functionJ NeurosciYear: 2001214600811425888
Rossi DJ,Oshima T,Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptakeNatureYear: 20004033162110659851
Thomson AM,Walker VE,Flynn DM. Glycine enhances NMDA-receptor mediated synaptic potentials in neocortical slicesNatureYear: 198933842242538754
Johnson JW,Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neuronsNatureYear: 1987325529312433595
Mothet JP,Parent AT,Wolosker H,Brady RO Jr,Linden DJ,Ferris CD. et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptorProc Natl Acad Sci U S AYear: 20009749263110781100
Kleckner NW,Dingledine R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytesScienceYear: 198824183572841759
Mayer ML,Westbrook GL,Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neuronesNatureYear: 198430926136325946
Monyer H,Sprengel R,Schoepfer R,Herb A,Higuchi M,Lomeli H,et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypesScienceYear: 19922561217211350383
Laube BJ,Kuhse ,Betz H. Evidence for a tetrameric structure of recombinant NMDA receptorsJ NeurosciYear: 1998182954619526012
Laube B,Hirai H,Sturgess M,Betz H,Kuhse J. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunitNeuronYear: 1997184935039115742
Kutsuwada T,Kashiwabuchi N,Mori H,Sakimura K,Kushiya E,Araki K,et al. Molecular diversity of the NMDA receptor channelNatureYear: 199235836411377365
Das S,Sasaki YF,Rothe T,Premkumar LS,Takasu M,Crandall JE,et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3ANatureYear: 1998393377819620802
Nakanishi N,Tu S,Shin Y,Cui J,Kurokawa T,Zhang D,et al. Neuroprotection by the NR3A subunit of the NMDA receptorJ NeurosciYear: 2009295260519386922
Sattler R,Xiong Z,Lu WY,Hafner M,MacDonald JF,Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 proteinScienceYear: 19992841845810364559
Bal-Price A,Brown GC. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicityJ NeurosciYear: 20012164809111517237
Cooper CE,Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiologyAm J Physiol Cell PhysiolYear: 2007292C1993200317329402
Lancaster JR Jr. Nitroxidative, nitrosative, and nitrative stress: kinetic predictions of reactive nitrogen species chemistry under biological conditionsChem Res ToxicolYear: 20061911607416978020
Yamashima T. Ca2+-dependent proteases in ischemic neuronal death: a conserved 'calpain–cathepsin cascade' from nematodes to primatesCell CalciumYear: 2004362859315261484
Rasola A,Bernardi P. Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosisCell CalciumYear: 2011502223321601280
Ikonomidou C,Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injuryLancet NeurolYear: 20021383612849400
Lee JM,Zipfel GJ,Choi DW. The changing landscape of ischaemic brain injury mechanismsNatureYear: 1999399A71410392575
Liu Y,Wong TP,Aarts M,Rooyakkers A,Liu L,Lai TW,et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivoJ NeurosciYear: 20072728465717360906
Hardingham GE,Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disordersNat Rev NeurosciYear: 2010116829620842175
Buchan AM,Lesiuk H,Barnes KA,Li H,Huang ZG,Smith KE,et al. AMPA antagonists: do they hold more promise for clinical stroke trials than NMDA antagonistsStrokeYear: 1993241148528342188
Sheardown MJ,Nielsen EO,Hansen AJ,Jacobsen P,Honoré T. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemiaScienceYear: 199024757142154034
Buchan AM,Li H,Cho S,Pulsinelli WA. Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult ratsNeurosci LettYear: 199113225581664505
Wenthold RJ,Petralia RS,Blahos J II,Niedzielski AS. Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neuronsJ NeurosciYear: 199616198298604042
Jonas P,Racca C,Sakmann B,Seeburg PH,Monyer H. Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expressionNeuronYear: 199412128198011338
Shi Y,Lu W,Milstein AD,Nicoll RA. The stoichiometry of AMPA receptors and TARPs varies by neuronal cell typeNeuronYear: 2009626334019524523
Burnashev N,Monyer H,Seeburg PH,Sakmann B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunitNeuronYear: 19928189981370372
Liu S,Lau L,Wei J,Zhu D,Zou S,Sun HS,et al. Expression of Ca2+-permeable AMPA receptor channels primes cell death in transient forebrain ischemiaNeuronYear: 200443435515233916
Hollmann M,Hartley M,Heinemann S. Ca2+ permeability of KA-AMPA — gated glutamate receptor channels depends on subunit compositionScienceYear: 199125285131709304
Verdoorn TA,Burnashev N,Monyer H,Seeburg PH,Sakmann B. Structural determinants of ion flow through recombinant glutamate receptor channelsScienceYear: 1991252171581710829
Noh KM,Yokota H,Mashiko T,Castillo PE,Zukin RS,Bennett MV. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia–induced deathProc Natl Acad Sci U S AYear: 200510212230516093311
Tanaka H,Grooms SY,Bennett MV,Zukin RS. The AMPAR subunit GluR2: still front and center–stageBrain ResYear: 200088619020711119696
Gorter JA,Petrozzino JJ,Aronica EM,Rosenbaum DM,Opitz T,Bennett MV,et al. Global ischemia induces downregulation of Glur2 mRNA and increases AMPA receptor-mediated Ca2+ influx in hippocampal CA1 neurons of gerbilJ NeurosciYear: 1997176179889236229
Pellegrini-Giampietro DE,Zukin RS,Bennett MV,Cho S,Pulsinelli WA. Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in ratsProc Natl Acad Sci U S AYear: 199289104995031438239
Zhou Y,Zhou L,Chen H,Koliatsos VE. An AMPA glutamatergic receptor activation — nitric oxide synthesis step signals transsynaptic apoptosis in limbic cortexNeuropharmacologyYear: 200651677616678219
Araujo IM,Verdasca MJ,Leal EC,Bahr BA,Ambrósio AF,Carvalho AP. et al. Early calpain-mediated proteolysis following AMPA receptor activation compromises neuronal survival in cultured hippocampal neuronsJ NeurochemYear: 20049113223115584909
Zhang QG,Han D,Hu SQ,Li C,Yu CZ,Wang R,et al. Positive modulation of AMPA receptors prevents downregulation of GluR2 expression and activates the Lyn-ERK1/2-CREB signaling in rat brain ischemiaHippocampusYear: 201020657719330848
Burnstock G. Physiology and pathophysiology of purinergic neurotransmissionPhysiol RevYear: 20078765979717429044
Matute C,Cavaliere F. Neuroglial interactions mediated by purinergic signalling in the pathophysiology of CNS disordersSemin Cell Dev BiolYear: 201122252921320622
Bolas NM,Rajagopalan B,Mitsumori F,Radda GK. Metabolic changes during experimental cerebral ischemia in hyperglycemic rats, observed by 31P and 1H magnetic resonance spectroscopyStrokeYear: 198819608143363594
Whittingham TS,Lust WD,Passonneau JV. An in vitro model of ischemia: metabolic and electrical alterations in the hippocampal sliceJ NeurosciYear: 198447938026323646
Katsura K,Rodriguez de Turco EB,Folbergrová J,Bazan NG,Siesjö BK. Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemiaJ NeurochemYear: 1993611677848228987
Frenguelli BG,Wigmore G,Llaudet E,Dale N. Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampusJ NeurochemYear: 200710114001317459147
Surprenant A,Rassendren F,Kawashima E,North RA,Buell G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7)ScienceYear: 199627273588614837
Le Feuvre RA,Brough D,Touzani O,Rothwell NJ. Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivoJ Cereb Blood Flow MetabYear: 200323381412621313
Skaper SD,Debetto P,Giusti P. The P2X7 purinergic receptor: from physiology to neurological disordersFASEB JYear: 2010243374519812374
Pelegrin P,Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptorEMBO JYear: 20062550718217036048
Locovei SJ,Wang J,Dahl G. Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calciumFEBS LettYear: 20065802394416364313
MacVicar BA,Thompson RJ. Non-junction functions of pannexin-1 channelsTrends NeurosciYear: 2010339310220022389
Juranyi ZB,Sperlagh B,Vizi ES. Involvement of P2 purinoceptors and the nitric oxide pathway in [3H]purine outflow evoked by short–term hypoxia and hypoglycemia in rat hippocampal slicesBrain ResYear: 19998231839010095025
Melani A,Turchi D,Vannucchi MG,Cipriani S,Gianfriddo M,Pedata F. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemiaNeurochem IntYear: 200547442816029911
Zhang Z,Chen G,Zhou W,Song A,Xu T,Luo Q,et al. Regulated ATP release from astrocytes through lysosome exocytosisNat Cell BiolYear: 200799455317618272
Iglesias R,Dahl G,Qiu F,Spray DC,Scemes E. Pannexin 1: the molecular substrate of astrocyte “hemichannels”J NeurosciYear: 2009297092719474335
Schock SC,Leblanc D,Hakim AM,Thompson CS. ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitroBiochem Biophys Res CommunYear: 20083681384418211823
Huckstepp RT,id Bihi R,Eason R,Spyer KM,Dicke N,Willecke K. et al. Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivityJ PhysiolYear: 201058839012020736421
Ballerini P,Di Iorio P,Ciccarelli R,Nargi E,D'Alimonte I,Traversa U. et al. Glial cells express multiple ATP binding cassette proteins which are involved in ATP releaseNeuroreportYear: 20021317899212395124
Darby M,Kuzmiski JB,Panenka W,Feighan D,MacVicar BA. ATP released from astrocytes during swelling activates chloride channelsJ NeurophysiolYear: 2003891870712686569
Chekeni FB,Elliott MR,Sandilos JK,Walk SF,Kinchen JM,Lazarowski ER,et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosisNatureYear: 2010467863720944749
Locovei S,Scemes E,Qiu F,Spray DC,Dahl G. Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complexFEBS LettYear: 2007581483817240370
Burnstock G,Krügel U,Abbracchio MP,Illes P. Purinergic signalling: from normal behaviour to pathological brain functionProg NeurobiolYear: 2011952297421907261
Cavaliere F,Amadio S,Dinkel K,Reymann KG,Volonté C. P2 receptor antagonist trinitrophenyl — adenosine-triphosphate protects hippocampus from oxygen and glucose deprivation cell deathJ Pharmacol Exp TherYear: 200732370717620457
Cavaliere F,Florenzano F,Amadio S,Fusco FR,Viscomi MT,D'Ambrosi N. et al. Up-regulation of P2X2, P2X4 receptor and ischemic cell death: prevention by P2 antagonistsNeuroscienceYear: 2003120859812849743
Cavaliere F,Sancesario G,Bernardi G,Volonté C. Extracellular ATP and nerve growth factor intensify hypoglycemia-induced cell death in primary neurons: role of P2 and NGFRp75 receptorsJ NeurochemYear: 20028311293812437584
Arbeloa J,Pérez-Samartín A,Gottlieb M,Matute C. P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemiaNeurobiol DisYear: 2012459546122186422
Domercq M,Perez-Samartin A,Aparicio D,Alberdi E,Pampliega O,Matute C. P2X7 receptors mediate ischemic damage to oligodendrocytesGliaYear: 2010587304020029962
Lammer A,Günther A,Beck A,Krügel U,Kittner H,Schneider D. et al. Neuroprotective effects of the P2 receptor antagonist PPADS on focal cerebral ischaemia-induced injury in ratsEur J NeurosciYear: 2006232824816817887
Lammer AB,Beck A,Grummich B,Förschler A,Krügel T,Kahn T. et al. The P2 receptor antagonist PPADS supports recovery from experimental stroke in vivoPLoS OneYear: 20116e1998321611146
Domercq M,Perez-Samartin A,Aparicio D,Alberdi E,Pampliega O,Matute C. P2X7 receptors mediate ischemic damage to oligodendrocytesGliaYear: 2010587304020029962
Traini C,Pedata F,Cipriani S,Mello T,Galli A,Giovannini MG,et al. P2 receptor antagonists prevent synaptic failure and extracellular signal-regulated kinase 1/2 activation induced by oxygen and glucose deprivation in rat CA1 hippocampus in vitroEur J NeurosciYear: 20113322031521453436
Dunwiddie TV. Endogenously released adenosine regulates excitability in the in vitro hippocampusEpilepsiaYear: 19802154187418669
Masino SA,Diao L,Illes P,Zahniser NR,Larson GA,Johansson B,et al. Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine a(1) receptorsJ Pharmacol Exp TherYear: 20023033566312235271
Malva JO,Silva AP,Cunha RA. Presynaptic modulation controlling neuronal excitability and epileptogenesis: role of kainate, adenosine and neuropeptide Y receptorsNeurochem ResYear: 20032815011514570395
Melani A,Cipriani S,Vannucchi MG,Nosi D,Donati C,Bruni P,et al. Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemiaBrainYear: 200913214809519359287
Chen GJ,Harvey BK,Shen H,Chou J,Victor A,Wang Y. Activation of adenosine A3 receptors reduces ischemic brain injury in rodentsJ Neurosci ResYear: 20068418485517016854
Braun N,Zhu Y,Krieglstein J,Culmsee C,Zimmermann H. Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the ratJ NeurosciYear: 19981848919009634555
Zimmermann H. Ectonucleotidases in the nervous systemNovartis Found SympYear: 200627611328discussion1283023372758116805426
Pedata F,Melani A,Pugliese AM,Coppi E,Cipriani S,Traini C. The role of ATP and adenosine in the brain under normoxic and ischemic conditionsPurinergic SignalYear: 2007329931018404443
Pugliese AM,Traini C,Cipriani S,Gianfriddo M,Mello T,Giovannini MG,et al. The adenosine A2A receptor antagonist ZM241385 enhances neuronal survival after oxygen-glucose deprivation in rat CA1 hippocampal slicesBr J PharmacolYear: 20091578183019422385
Daval JL,Von Lubitz DK,Deckert J,Redmond DJ,Marangos PJ. Protective effect of cyclohexyladenosine on adenosine A1-receptors, guanine nucleotide and forskolin binding sites following transient brain ischemia: a quantitative autoradiographic studyBrain ResYear: 1989491212262504437
Von Lubitz DK,Lin RC,Melman N,Ji XD,Carter MF,Jacobson KA. Chronic administration of selective adenosine A1 receptor agonist or antagonist in cerebral ischemiaEur J PharmacolYear: 199425616178050467
Von Lubitz DK,Lin RC,Popik P,Carter MF,Jacobson KA. Adenosine A3 receptor stimulation and cerebral ischemiaEur J PharmacolYear: 199426359677821362
Von Lubitz DK,Lin RC,Melman N,Ji XD,Carter MF,Jacobson KA. Chronic NMDA receptor stimulation: therapeutic implications of its effect on adenosine A1 receptorsEur J PharmacolYear: 1995283185927498308
Von Lubitz DK,Lin RC,Jacobson KA. Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonistEur J PharmacolYear: 19952872953028991804
Von Lubitz DK,Lin RC,Paul IA,Beenhakker M,Boyd M,Bischofberger N. et al. Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbilsEur J PharmacolYear: 199631617198982684
Monopoli A,Lozza G,Forlani A,Mattavelli A,Ongini E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in ratsNeuroreportYear: 19989395599875735
Cassada DC,Tribble CG,Laubach VE,Nguyen BN,Rieger JM,Linden J,et al. An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusionJ Vasc SurgYear: 200134482811533601
Latini S,Bordoni F,Corradetti R,Pepeu G,Pedata F. Effect of A2A adenosine receptor stimulation and antagonism on synaptic depression induced by in vitro ischaemia in rat hippocampal slicesBr J PharmacolYear: 199912810354410556941
Pugliese AM,Coppi E,Spalluto G,Corradetti R,Pedata F. A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitroBr J PharmacolYear: 20061475243216415905
Pugliese AM,Coppi E,Volpini R,Cristalli G,Corradetti R,Jeong LS,et al. Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen-glucose deprivation episodes of different durationBiochem PharmacolYear: 2007747687917626785
Chen JF,Huang Z,Ma J,Zhu J,Moratalla R,Standaert D,et al. A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in miceJ NeurosciYear: 199919919220010531422
Panchin Y,Kelmanson I,Matz M,Lukyanov K,Usman N,Lukyanov S. A ubiquitous family of putative gap junction moleculesCurr BiolYear: 200010R473410898987
Baranova A,Ivanov D,Petrash N,Pestova A,Skoblov M,Kelmanson I,et al. The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteinsGenomicsYear: 2004837061615028292
Swayne LA,Sorbara CD,Bennett SA. Pannexin 2 is expressed by postnatal hippocampal neural progenitors and modulates neuronal commitmentJ Biol ChemYear: 2010285249778620529862
Thompson RJ,Zhou N,MacVicar BA. Ischemia opens neuronal gap junction hemichannelsScienceYear: 2006312924716690868
Zhang L,Deng T,Sun Y,Liu K,Yang Y,Zheng X. Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivationJ Neurosci ResYear: 20088622819118381763
Bunse S,Schmidt M,Prochnow N,Zoidl G,Dermietzel R. Intracellular cysteine 346 is essentially involved in regulating Panx1 channel activityJ Biol ChemYear: 2010285384445220829356
Bargiotas P,Krenz A,Hormuzdi SG,Ridder DA,Herb A,Barakat W,et al. Pannexins in ischemia-induced neurodegenerationProc Natl Acad Sci U S AYear: 201110820772722147915
Locovei S,Bao L,Dahl G. Pannexin 1 in erythrocytes: function without a gapProc Natl Acad Sci U S AYear: 20061037655916682648
Chekeni FB,Elliott MR,Sandilos JK,Walk SF,Kinchen JM,Lazarowski ER,et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosisNatureYear: 2010467863720944749
Wicki-Stordeur LE,Dzugalo AD,Swansburg RM,Suits JM. Pannexin 1 regulates postnatal neural stem and progenitor cell proliferationNeural DevYear: 201271122458943
Thompson RJ,Jackson MF,Olah ME,Rungta RL,Hines DJ,Beazely MA. et al. Activation of pannexin-1 hemichannels augments aberrant bursting in the hippocampusScienceYear: 20083221555919056988
Vessey DA,Li L,Kelley M. Ischemic preconditioning requires opening of pannexin-1/P2X(7) channels not only during preconditioning but again after index ischemia at full reperfusionMol Cell BiochemYear: 2011351778421267638
Gulbransen BD,Bashashati M,Hirota SA,Gui X,Roberts JA,MacDonald JA. et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitisNat MedYear: 2012Mar18. doi: 10.1038/nm.2679
Iglesias R,Locovei S,Roque A,Alberto AP,Dahl G,Spray DC,et al. P2X7 receptor-Pannexin1 complex: pharmacology and signalingAm J Physiol Cell PhysiolYear: 2008295C7526018596211
Qiu F,Dahl G. A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATPAm J Physiol Cell PhysiolYear: 2009296C250518945939
Pelegrin P,Barroso-Gutierrez C,Surprenant A. P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophageJ ImmunolYear: 200818071475718490713
Lennmyr F,Ericsson A,Gerwins P,Akterin S,Ahlström H,Terént A. Src family kinase-inhibitor PP2 reduces focal ischemic brain injuryActa Neurol ScandYear: 2004110175915285775
Liang S,Pong K,Gonzales C,Chen Y,Ling HP,Mark RJ,et al. Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemiaJ Pharmacol Exp TherYear: 20093318273519741150
Tian HP,Huang BS,Zhao J,Hu XH,Guo J,Li LX. Non-receptor tyrosine kinase Src is required for ischemia-stimulated neuronal cell proliferation via Raf/ERK/CREB activation in the dentate gyrusBMC NeurosciYear: 20091013919943942
Guo J,Adato R. Extended long range plasmon waves in finite thickness metal film and layered dielectric materialsOpt ExpressYear: 200614124091819529673
Kawamura M Jr,Ruskin DN,Masino SA. Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channelsJ NeurosciYear: 20103038869520237259
Sandilos JK,Chiu YH,Chekeni FB,Armstrong AJ,Walk SF,Ravichandran KS,et al. Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C terminal autoinhibitory regionJ Biol ChemYear: 2012287113031122311983
Santiago MF,Veliskova J,Patel NK,Lutz SE,Caille D,Charollais A,et al. Targeting pannexin1 improves seizure outcomePLoS OneYear: 20116e2517821949881
Clapham DE,Runnels LW,Strubing C. The TRP ion channel familyNature reviewsNeuroscienceYear: 2001238796
Wu LJ,Sweet TB,Clapham DE. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel familyPharmacol RevYear: 20106238140420716668
Aarts M,Iihara K,Wei WL,Xiong ZG,Arundine M,Cerwinski W,et al. A key role for TRPM7 channels in anoxic neuronal deathCellYear: 20031158637714697204
Miller BA. Inhibition of TRPM2 function by PARP inhibitors protects cells from oxidative stress-induced deathBr J PharmacolYear: 2004143515615514246
MacDonald JF,Xiong ZG,Jackson MF. Paradox of Ca2+ signaling, cell death and strokeTrends NeurosciYear: 200629758116376999
Aarts MM,Tymianski M. TRPMs and neuronal cell deathPflugers ArchYear: 2005451243916044308
Perraud AL,Fleig A,Dunn CA,Bagley LA,Launay P,Schmitz C,et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homologyNatureYear: 2001411595911385575
Harteneck C. Function and pharmacology of TRPM cation channelsNaunyn Schmiedebergs Arch PharmacolYear: 20053713071415843919
Simard JM,Tarasov KV,Gerzanich V. Non-selective cation channels, transient receptor potential channels and ischemic strokeBiochim Biophys ActaYear: 200717729475717446049
Cook DJ,Teves L,Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brainNatureYear: 2012483213722388811
Sun HS,Jackson MF,Martin LJ,Jansen K,Teves L,Cui H,et al. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemiaNat NeurosciYear: 2009121300719734892
Montell C,Birnbaumer L,Flockerzi V. The TRP channels, a remarkably functional familyCellYear: 2002108595811893331
Zhang W,Chu X,Tong Q,Cheung JY,Conrad K,Masker K,et al. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell deathJ Biol ChemYear: 200327816222912594222
Fonfria E,Mattei C,Hill K,Brown JT,Randall A,Benham CD,et al. TRPM2 is elevated in the tMCAO stroke model, transcriptionally regulated, and functionally expressed in C13 microgliaJ Recept Signal Transduct ResYear: 2006261799816777714
Xiong ZG,Chu XP,Simon RP. Ca2+-permeable acid-sensing ion channels and ischemic brain injuryJ Membr BiolYear: 2006209596816685601
Isaev NK,Stelmashook EV,Plotnikov EY,Khryapenkova TG,Lozier ER,Doludin YV,et al. Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemiaBiochemistry (Mosc)Year: 2008731171519120019
Xiong ZG,Zhu XM,Chu XP,Minami M,Hey J,Wei WL,et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channelsCellYear: 20041186879815369669
Yermolaieva O,Leonard AS,Schnizler MK,Abboud FM,Welsh MJ. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1aProc Natl Acad Sci U S AYear: 20041016752715082829
Krishtal O. The ASICs: signaling molecules? ModulatorsTrends NeurosciYear: 2003264778312948658
Waldmann R,Champigny G,Bassilana F,Heurteaux C,Lazdunski M. A proton-gated cation channel involved in acid-sensingNatureYear: 199738617379062189
Gonzales EB,Kawate T,Gouaux E. Pore architecture and ion sites in acid-sensing ion channels and P2X receptorsNatureYear: 200946059960419641589
Jasti J,Furukawa H,Gonzales EB,Gouaux E. Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pHNatureYear: 20074493162317882215
Paukert M,Chen X,Polleichtner G,Schindelin H. Gründer S. Candidate amino acids involved in H+ gating of acid-sensing ion channel 1aJ Biol ChemYear: 20082835728117981796
Grunder S,Chen X. Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1aInt J Physiol Pathophysiol PharmacolYear: 20102739421383888
Pignataro G,Simon RP,Xiong ZG. Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemiaBrainYear: 2007130151817114797
Gao J,Duan B,Wang DG,Deng XH,Zhang GY,Xu L,et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal deathNeuronYear: 2005486354616301179
Duan B,Wang YZ,Yang T,Chu XP,Yu Y,Huang Y,et al. Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosisJ NeurosciYear: 20113121011221307247
Sherwood TW,Askwith CC. Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal deathJ NeurosciYear: 200929143718019906984

Article Categories:
  • Review

Keywords: stroke, anoxic depolarization, ionotropic receptors, NMDA receptors, P2X7 receptors, ion channels, pannexin channels, TRP channels, acid-sensing ion channels (ASICs).

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