Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism

Park, Eun Chan; Ghose, Piya; Shao, Zhiyong; Ye, Qi; Kang, Lijun; Xu, X.Z. Shawn; Powell-Coffman, Jo Anne; Rongo, Christopher

doi:10.1038/emboj.2011.499

Cited by 53 publications

(54 citation statements)

References 79 publications

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“…The downregulation of rabaptin-5 has been shown to be mediated by HIF. In contrast, Park et al (2012) showed recently that hypoxia reduces the cell surface expression of the glutamate receptor through an HIF-1-independent mechanism. In line with this study, we demonstrated that HIF-1α knockdown did not affect the hypoxia-induced reduction of Hsp70 membrane expression in MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 94%

A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

Schilling

Tetzlaff

Konrad

et al. 2015

Cell Stress and Chaperones

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Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and B (MICA/B) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1α (HIF-1α) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1α levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDA-MB-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1α in H1339 cells with high basal HIF-1α levels. Hypoxia and HIF-1α did not affect the MICA/B expression in MDA-MB-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1α in MDA-MB-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only MICA/B appears to be regulated by HIF-1α.

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Section: Discussionmentioning

confidence: 94%

A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

Schilling

Tetzlaff

Konrad

et al. 2015

Cell Stress and Chaperones

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“…Interestingly, unlike in classical HIF‐dependent hypoxic responses, neuronal EGL‐9 interacts with the GLR‐1 recycling mediator LIN‐10 (a PTB/PDZ domain protein) to promote its relocalization away from the plasma membrane. This effect of hypoxia requires the CDK‐5 kinase (Park et al ., ).…”

Section: New Targets Regulated By Prolyl Hydroxylase Enzymesmentioning

confidence: 97%

“…Under hypoxic conditions, EGL‐9 becomes inefficient and has less interaction with LIN‐10, whose serine or threonine residues are phosphorylated by CDK‐5. Phosphorylated LIN‐10 reduces glutamate signalling by enhancing the recruitment of GLR‐1 to endosomes (Park et al ., ). Finally, this suppresses nematode foraging behaviour.…”

Section: New Targets Regulated By Prolyl Hydroxylase Enzymesmentioning

confidence: 97%

“…Finally, this suppresses nematode foraging behaviour. As low oxygen could induce massive synaptic vesicle exocytosis at the presynaptic terminus, this mechanism protects nematode neurones from glutamate excitotoxicity (Park et al ., ), a common mechanism of neural cell death. This mechanism is central to ischemic stroke, and targeting the EGL‐9/LIN‐10/GLR‐1 pathway may lead to future therapies.…”

Section: New Targets Regulated By Prolyl Hydroxylase Enzymesmentioning

confidence: 99%

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Current advances in the novel functions of hypoxia‐inducible factor and prolyl hydroxylase in invertebrates

Wang

Cui

et al. 2015

Insect Molecular Biology

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Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia-inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs). However, recent findings have uncovered novel HIF-independent functions of PHDs. This review provides an overview of how invertebrates are able to sustain hypoxic damages, and highlights some recent discoveries in the regulation of cellular signalling by PHDs. Given that some core genes and major pathways are evolutionarily conserved, these research findings could provide insight into oxygen-sensitive signalling in mammals, and have biomedical implications for human diseases.

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“…Recent work in Caenorhabditis elegans highlights a role for hypoxia and PHDs in the regulation of AMPA receptor trafficking and activity and which may decrease the availability and function of AMPA receptors in the post‐synaptic membrane (Park et al . ). This might explain the inhibitory effects of acute PHD inhibition on LTP in mice (Corcoran et al .…”

Section: Effect Of Acute Hypoxia and Hif Stabilizers On Neuronal Signmentioning

confidence: 97%

Hypoxia‐inducible factor signalling mechanisms in the central nervous system

Corcoran

O’Connor

2013

Acta Physiologica

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In the CNS, neurones are highly sensitive to the availability of oxygen. In conditions where oxygen availability is decreased, neuronal function can be altered, leading to injury and cell death. Hypoxia has been implicated in a number of central nervous system pathologies including stroke, head trauma and neurodegenerative diseases. Cellular responses to oxygen deprivation are complex and result in activation of short‐ and long‐term mechanisms to conserve energy and protect cells. Failure of synaptic transmission can be observed within minutes following this hypoxia. The acute effects of hypoxia on synaptic transmission are primarily mediated by altering ion fluxes across membranes, pre‐synaptic effects of adenosine and other actions at glutamatergic receptors. A more long‐term feature of the response of neurones to hypoxia is the activation of transcription factors such as hypoxia‐inducible factor. The activation of hypoxia‐inducible factor is governed by a family of dioxygenases called hypoxia‐inducible factor prolyl 4 hydroxylases (PHDs). Under hypoxic conditions, PHD activity is inhibited, thereby allowing hypoxia‐inducible factor to accumulate and translocate to the nucleus, where it binds to the hypoxia‐responsive element sequences of target gene promoters. Inhibition of PHD activity stabilizes hypoxia‐inducible factor and other proteins thus acting as a neuroprotective agent. This review will focus on the response of neuronal cells to hypoxia‐inducible factor and its targets, including the prolyl hydroxylases. We also present evidence for acute effects of PHD inhibition on synaptic transmission and plasticity in the hippocampus.

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Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism

Cited by 53 publications

References 79 publications

A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

Current advances in the novel functions of hypoxia‐inducible factor and prolyl hydroxylase in invertebrates

Hypoxia‐inducible factor signalling mechanisms in the central nervous system

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