Zinc: new clues to diverse roles in brain ischemia

Shuttleworth, C. William; Weiss, John H.

doi:10.1016/j.tips.2011.04.001

Cited by 154 publications

(135 citation statements)

References 80 publications

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…These results confirm Zn 2 + release from an intracellular source. Previous studies suggested that oxidants trigger Zn 2 + release from metallothioneins, proteins that have a strong buffering capacity for cytosolic Zn 2 + [20,21,31]. However, the finding that PJ34 and 2-APB are able to prevent H 2 O 2 -induced Zn 2 + response ( Figures 1D and 1E) suggests that Zn 2 + release occurs by a specific mechanism, requiring TRPM2 channel activation.…”

Section: The Source Of Trpm2-targeted Zn 2 + Stores Is Intracellularmentioning

confidence: 84%

“…This effect was suppressed by PJ34 and 2-APB (Figures 1D and 1E; Supplementary Figures S3C and S3D), suggesting that TRPM2 activation contributes to the rise in cytosolic Zn 2 + . To test whether this rise in Zn 2 + contributes to cell death, we used TPEN (1 μM) [20,21] and clioquinol (10 μM) [29] at concentrations at which they chelate Zn 2 + , but can hardly bind Ca 2 + . Both reagents effectively prevented cell death ( Figures 1F and 1G).…”

Section: β-Cell Apoptosis Results From Trpm2-mediated Rise In Cytosolmentioning

confidence: 99%

“…Free Zn 2 + is highly toxic to cells. For this reason, cytoplasmic Zn 2 + is either buffered by metallothioneins or sequestered into organelles [20,21]. It has been widely reported that oxidative stress triggers Zn 2 + release from metallothioneins through nonspecific protein oxidation [20,21,31].…”

Section: Discussionmentioning

confidence: 99%

“…To confirm that at this concentration, TPEN chelates Zn 2 + only, we have tested the ability of the chelator to quench fluorescence resulting from metal ion binding to Fluo-4 and FluoroZin-3 ( Figures 3F and 3G). TPEN caused a small, but significant, decrease in Fluo-4 fluorescence, a decrease that could be attributed to the exceptional ability of Fluo-4 to bind Zn 2 + , co-released [20,21]. The TPEN-insensitive Fluo-4 signal can be attributed to Ca 2 + binding to the probe.…”

Section: The Source Of Trpm2-targeted Zn 2 + Stores Is Intracellularmentioning

confidence: 91%

“…Interestingly, a previous study demonstrated that TRPM2 channels can be permeate by Zn 2 + ions [19]. Although the relevance of this function to cell death has not yet been examined, Zn 2 + is a bona fide cytotoxic ion [20,21] and could also contribute to TRPM2-mediated β-cell death.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca 2 + . Recent studies however revealed that TRPM2 channels can also conduct Zn 2 + , but the physiological relevance of this property is enigmatic. Given that Zn 2 + is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn 2 + to affect cell viability. To address this, we used the insulin secreting (INS1) β-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H 2 O 2 activation of TRPM2 channels increases the cytosolic levels of both Ca 2 + and Zn 2 + and causes apoptotic cell death. Interestingly, chelation of Zn 2 + alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn 2 + is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn 2 + release. Zn 2 + release is potentiated by extracellular Ca 2 + entry, indicating that Ca 2 + -induced Zn 2 + release leads to apoptosis. Knockout of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca 2 + -potentiated Zn 2 + release underlies ROS-induced β-cell death and Zn 2 + , rather than Ca 2 + , plays a primary role in apoptosis.

show abstract

Section: The Source Of Trpm2-targeted Zn 2 + Stores Is Intracellularmentioning

confidence: 84%

Section: β-Cell Apoptosis Results From Trpm2-mediated Rise In Cytosolmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Source Of Trpm2-targeted Zn 2 + Stores Is Intracellularmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

show abstract

Electrospun Fibers as a Solid‐State Real‐Time Zinc Ion Sensor with High Sensitivity and Cell Medium Compatibility

Syu

Cheng

Hong

et al. 2012

Adv Funct Materials

View full text Add to dashboard Cite

Abstractmeso‐2,6‐Dichlorophenyltripyrrinone (TPN‐Cl2), a probe molecule for zinc II ions, is dispersed in a polymer host. The red fluorescence peak at 620 nm appears when the molecule forms a complex with zinc at its center. TPN‐Cl2 has a high selectivity for zinc II and tolerates many common metal ions present in the human body. The probe molecules are blended with a hydrogel polymer, poly(2‐hydroxyethyl methacrylate) (poly HEMA), with 30 wt% dimethylformamide (DMF). The fiber structure with 1 μm diameter is made by electrospinning in DMF solution of the probe and poly HEMA mixture. The fibrous film detects zinc ions with concentrations as low as 10−6 M in real‐time both in water and in the commonly used cell culture liquid media Dulbecco's modified Eagle medium (DMEM) and fetal bovine serum (FBS), which contain many metal ions and proteins. The time‐resolution is 5 min for 10−6 M and 1 min for 10−5 M. This sensitivity and response speed satisfy the requirements for non‐invasive biomedical studies.

show abstract

Zn²⁺‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes

Domercq

Mato

Soria

et al. 2012

Glia

View full text Add to dashboard Cite

Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca(2+)](i), loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the oxygen paradox). Herein we describe a novel signaling pathway that is activated during ischemia-like conditions (oxygen and glucose deprivation; OGD) and contributes to ischemia-induced oligodendroglial cell death. OGD induced a retarded and sustained increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after restoring glucose and O(2) (reperfusion-like conditions). Blocking the ERK1/2 pathway with the MEK inhibitor UO126 largely protected oligodendrocytes against ischemic insults. ERK1/2 activation was blocked by the high-affinity Zn(2+) chelator TPEN, but not by antagonists of AMPA/kainate or P2X7 receptors that were previously shown to be involved in ischemic oligodendroglial cell death. Using a high-affinity Zn(2+) probe, we showed that ischemia induced an intracellular Zn(2+) rise in oligodendrocytes, and that incubation with TPEN prevented mitochondrial depolarization and ROS generation after ischemia. Accordingly, exposure to TPEN and the antioxidant Trolox reduced ischemia-induced oligodendrocyte death. Moreover, UO126 blocked the ischemia-induced increase in poly-[ADP]-ribosylation of proteins, and the poly[ADP]-ribose polymerase 1 (PARP-1) inhibitor DPQ significantly inhibited ischemia-induced oligodendroglial cell death-demonstrating that PARP-1 was required downstream in the Zn(2+)-ERK oligodendrocyte cell death pathway. Chelation of cytosolic Zn(2+), blocking ERK signaling, and antioxidants may be beneficial for treating CNS white matter ischemia-reperfusion injury. Importantly, all the inhibitors of this pathway protected oligodendrocytes when applied after the ischemic insult.

show abstract

Zinc: new clues to diverse roles in brain ischemia

Cited by 154 publications

References 80 publications

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Electrospun Fibers as a Solid‐State Real‐Time Zinc Ion Sensor with High Sensitivity and Cell Medium Compatibility

Zn²⁺‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes

Contact Info

Product

Resources

About

Zinc: new clues to diverse roles in brain ischemia

Cited by 154 publications

References 80 publications

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Electrospun Fibers as a Solid‐State Real‐Time Zinc Ion Sensor with High Sensitivity and Cell Medium Compatibility

Zn2+‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes

Contact Info

Product

Resources

About

Zn²⁺‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes