New Insights into the Crosstalk Between NMDARs and Iron: Implications for Understanding Pathology of Neurological Diseases

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2017 Apr 1

PMID 28360837

Citations 10

Authors

Huamin Xu

Hong Jiang

Junxia Xie

Affiliations

Soon will be listed here.

Abstract

Both iron dyshomeostasis and N-methyl-D-aspartate receptors (NMDARs)-mediated neurotoxicity have been shown to have an important role in neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence proved that activation of NMDARs could promote iron overload and iron-induced neurotoxicity by enhancing iron importer divalent metal transporter 1 (DMT1)-mediated iron uptake and iron releasing from lysosome. Also, iron overload could regulate NMDARs-mediated synaptic transmission. This indicates that there might be a possible relationship between iron and activation of NMDARs in neurological diseases. Understanding this interaction between iron and activation of NMDARs may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for these diseases. Therefore, in this review article, we will describe the dysfunction of iron metabolism and NMDARs in neurological diseases including PD and AD, and summarize the new insight into the mechanisms underlying the interaction between iron and activation of NMDARs.

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References

Altamura S, Muckenthaler M . Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis. J Alzheimers Dis. 2009; 16(4):879-95. DOI: 10.3233/JAD-2009-1010. View

Schiemann J, Schlaudraff F, Klose V, Bingmer M, Seino S, Magill P . K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci. 2012; 15(9):1272-80. PMC: 4242970. DOI: 10.1038/nn.3185. View

Carvajal F, Mattison H, Cerpa W . Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies. Neural Plast. 2016; 2016:2701526. PMC: 5007376. DOI: 10.1155/2016/2701526. View

Zhang S, Wang J, Song N, Xie J, Jiang H . Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging. 2008; 30(9):1466-76. DOI: 10.1016/j.neurobiolaging.2007.11.025. View

Bading H . Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. J Exp Med. 2017; 214(3):569-578. PMC: 5339681. DOI: 10.1084/jem.20161673. View

Hubert N, Hentze M . Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002; 99(19):12345-50. PMC: 129447. DOI: 10.1073/pnas.192423399. View

Courtney M, Li L, Lai Y . Mechanisms of NOS1AP action on NMDA receptor-nNOS signaling. Front Cell Neurosci. 2014; 8:252. PMC: 4145862. DOI: 10.3389/fncel.2014.00252. View

Oster S, Radad K, Scheller D, Hesse M, Balanzew W, Reichmann H . Rotigotine protects against glutamate toxicity in primary dopaminergic cell culture. Eur J Pharmacol. 2013; 724:31-42. DOI: 10.1016/j.ejphar.2013.12.014. View

Ganz T . Cellular iron: ferroportin is the only way out. Cell Metab. 2005; 1(3):155-7. DOI: 10.1016/j.cmet.2005.02.005. View

10.

Abboud S, Haile D . A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000; 275(26):19906-12. DOI: 10.1074/jbc.M000713200. View

11.

Perry G, Taddeo M, Petersen R, Castellani R, Harris P, Siedlak S . Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease. Biometals. 2003; 16(1):77-81. DOI: 10.1023/a:1020731021276. View

12.

Kostka M, Hogen T, Danzer K, Levin J, Habeck M, Wirth A . Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem. 2008; 283(16):10992-1003. DOI: 10.1074/jbc.M709634200. View

13.

Carlson E, Tkac I, Magid R, OConnor M, Andrews N, Schallert T . Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr. 2009; 139(4):672-9. PMC: 2666361. DOI: 10.3945/jn.108.096354. View

14.

Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds G, Hebenstreit G . Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm. 1988; 74(3):199-205. DOI: 10.1007/BF01244786. View

15.

Koles L, Kato E, Hanuska A, Zadori Z, Al-Khrasani M, Zelles T . Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems. Purinergic Signal. 2015; 12(1):1-24. PMC: 4749532. DOI: 10.1007/s11302-015-9480-5. View

16.

Errico F, Santini E, Migliarini S, Borgkvist A, Centonze D, Nasti V . The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons. Mol Cell Neurosci. 2007; 37(2):335-45. DOI: 10.1016/j.mcn.2007.10.007. View

17.

Okazaki Y, Ma Y, Yeh M, Yin H, Li Z, Yeh K . DMT1 (IRE) expression in intestinal and erythroid cells is regulated by peripheral benzodiazepine receptor-associated protein 7. Am J Physiol Gastrointest Liver Physiol. 2012; 302(10):G1180-90. PMC: 3362094. DOI: 10.1152/ajpgi.00545.2010. View

18.

Munoz P, Humeres A, Elgueta C, Kirkwood A, Hidalgo C, Nunez M . Iron mediates N-methyl-D-aspartate receptor-dependent stimulation of calcium-induced pathways and hippocampal synaptic plasticity. J Biol Chem. 2011; 286(15):13382-92. PMC: 3075684. DOI: 10.1074/jbc.M110.213785. View

19.

Han M, Kim J . Effect of dietary iron loading on recognition memory in growing rats. PLoS One. 2015; 10(3):e0120609. PMC: 4352024. DOI: 10.1371/journal.pone.0120609. View

20.

Rogers J, Randall J, Cahill C, Eder P, Huang X, Gunshin H . An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem. 2002; 277(47):45518-28. DOI: 10.1074/jbc.M207435200. View