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Voltage-gated Calcium Channels Provide an Alternate Route for Iron Uptake in Neuronal Cell Cultures

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Abstract

Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. VGCCs, ubiquitously expressed, may be an important route of excessive entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of 45Ca2+ and 55Fe2+ into NGF-treated rat PC12, and murine N-2α cells. Iron not only competed with calcium for entry into these cells, but iron uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176, an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.

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Abbreviations

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

VGCC:

Voltage-gated calcium channel

ROS:

Reactive oxygen species

NGF:

Nerve growth factor

ICH:

Intracerebral hemorrhage

SAH:

Subarachnoid hemorrhage

Tf:

Transferrin

CSF:

Cerebrospinal fluid

IF:

Interstitial fluid

Lf:

Lactoferrin

DMT-1:

Divalent metal transporter-1

References

  1. Connor JR, Menzies SL, Burdo JR, Boyer PJ (2001) Iron and iron management proteins in neurobiology. Pediatr Neurol 25:118–129

    Article  PubMed  CAS  Google Scholar 

  2. Berg D, Gerlach M, Youdim MBH, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron pathways and their relevance to Parkinson’s disease. J Neurochem 79:225–236

    Article  PubMed  CAS  Google Scholar 

  3. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873

    Article  PubMed  CAS  Google Scholar 

  4. Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cerebr Blood Flow Metab 23:629–652

    CAS  Google Scholar 

  5. Palmer C, Menzies SL, Roberts RL, Pavlick G, Connor JR (1999) Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J Neurosci Res 56:60–71

    Article  PubMed  CAS  Google Scholar 

  6. Umbreit JN, Conrad ME, Moore EG, Latour LF (1998) Iron absorption and cellular transport: the mobilferrin/paraferritin paradigm. Semin Hematol 35:13–26

    PubMed  CAS  Google Scholar 

  7. Moos T, Morgan EH (2004) The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann N Y Acad Sci 1012:14–26

    Article  PubMed  CAS  Google Scholar 

  8. Qian ZM, Shen X (2001) Brain iron transport and neurodegeneration. Trends Mol Med 7:103–108

    Article  PubMed  CAS  Google Scholar 

  9. Connor JR, Menzies SL, St Martin S, Mufson E (1990) Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res 27:595–611

    Article  PubMed  CAS  Google Scholar 

  10. Kissel K, Hamm S, Schulz M, Vecchi A, Garlanda C, Engelhardt B (1998) Immunohistochemical localization of the murine transferrin receptor (TfR) on blood-tissue barriers using a novel anti-TfR monoclonal antibody. Histochem Cell Biol 110:63–72

    Article  PubMed  CAS  Google Scholar 

  11. Dickinson TK, Connor JR (1998) Immunohistochemical analysis of transferrin receptor: regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain. Brain Res 801:171–181

    Article  PubMed  CAS  Google Scholar 

  12. Bradbury MW (1997) Transport of iron in the blood-brain-cerebrospinal fluid system. J Neurochem 69:443–454

    Article  PubMed  CAS  Google Scholar 

  13. Aisen P, Wessling-Resnick M, Leibold EA (1999) Iron metabolism. Curr Opin Chem Biol 3:200–206

    Article  PubMed  CAS  Google Scholar 

  14. Dickinson TK, Connor JR (1995) Cellular distribution of iron, transferrin, and ferritin in the hypotransferrinemic (Hp) mouse brain. J Comp Neurol 355:67–80

    Article  PubMed  CAS  Google Scholar 

  15. Moos T, Trinder D, Morgan EH (2000) Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta2-microglobulin deficient mouse brain. Cell Mol Biol (Noisy-le-grand) 46:549–561

    CAS  Google Scholar 

  16. Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH (2003) L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 9:1187–1194

    Article  PubMed  CAS  Google Scholar 

  17. Crowe S, Bartfay WJ (2002) Amlodipine decreases iron uptake and oxygen free radical production in the heart of chronically iron overloaded mice. Biol Res Nurs 3:189–197

    PubMed  Google Scholar 

  18. Scriabine A, Van den Kerckhoff W (1988) Pharmacology of nimodipine. A review. Ann N Y Acad Sci 522:698–706

    Article  PubMed  CAS  Google Scholar 

  19. Zheng W, Rampe D, Triggle DJ (1991) Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations. Mol Pharmacol 40:734–741

    PubMed  CAS  Google Scholar 

  20. Rampe D, Dage RC (1992) Functional interactions between two Ca2+ channel activators, (S)-Bay K 8644 and FPL 64176, in smooth muscle. Mol Pharmacol 41:599–602

    PubMed  CAS  Google Scholar 

  21. Kunze DL, Rampe D (1992) Characterization of the effects of a new Ca2+ channel activator, FPL 64176, in GH3 cells. Mol Pharmacol 42:666–670

    PubMed  CAS  Google Scholar 

  22. Calderon FH, Bonnefont A, Munoz FJ, Fernandez V, Videla LA, Inestrosa NC (1999) PC12 and neuro 2a cells have different susceptibilities to acetylcholinesterase-amyloid complexes, amyloid25-35 fragment, glutamate, and hydrogen peroxide. J Neurosci Res 56:620–631

    Article  PubMed  CAS  Google Scholar 

  23. Usowicz MM, Porzig H, Becker C, Reuter H (1990) Differential expression by nerve growth factor of two types of Ca2+ channels in rat phaeochromocytoma cell lines. J Physiol 426:95–116

    PubMed  CAS  Google Scholar 

  24. Garber SS, Hoshi T, Aldrich RW (1989) Regulation of ionic currents in pheochromocytoma cells by nerve growth factor and dexamethasone. J Neurosci 9:3976–3987

    PubMed  CAS  Google Scholar 

  25. Powers JF, Evinger MJ, Tsokas P, Bedri S, Alroy J, Shahsavari M, Tischler AS (2000) Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice. Cell Tissue Res 302:309–320

    Article  PubMed  CAS  Google Scholar 

  26. Wu GS, Vaswani KK, Lu ZH, Ledeen RW (1990) Gangliosides stimulate calcium flux in neuro-2A cells and require exogenous calcium for neuritogenesis. J Neurochem 55:484–491

    Article  PubMed  CAS  Google Scholar 

  27. Herman MD, Reuveny E, Narahashi T (1993) The effect of polyamines on voltage-activated calcium channels in mouse neuroblastoma cells. J Physiol 462:645–660

    PubMed  CAS  Google Scholar 

  28. Carlson RO, Masco D, Brooker G, Spiegel S (1994) Endogenous ganglioside GM1 modulates L-type calcium channel activity in N18 neuroblastoma cells. J Neurosci 14:2272–2281

    PubMed  CAS  Google Scholar 

  29. Liu L, Gonzalez PK, Barrett CF, Rittenhouse AR (2003) The calcium channel ligand FPL 64176 enhances L-type but inhibits N-type neuronal calcium currents. Neuropharmacol 45:281–292

    Article  CAS  Google Scholar 

  30. McDonough SI, Mori Y, Bean BP (2005) FPL 64176 modification of Ca(V)1.2 L-type calcium channels: dissociation of effects on ionic current and gating current. Biophys J 88:211–223

    Article  PubMed  CAS  Google Scholar 

  31. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K (1995) Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 45:182–184

    PubMed  CAS  Google Scholar 

  32. Berg D, Hochstrasser H, Schweitzer KJ, Riess O (2006) Disturbance of iron metabolism in Parkinson’s disease - ultrasonography as a biomarker. Neurotox Res 9:1–13

    Article  PubMed  CAS  Google Scholar 

  33. Faucheux BA, Martin ME, Beaumont C, Hauw JJ, Agid Y, Hirsch EC (2003) Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease. J Neurochem 86:1142–1148

    Article  PubMed  CAS  Google Scholar 

  34. Jurma OP, Hom DG, Andersen JK (1997) Decreased glutathione results in calcium-mediated cell death in PC12. Free Radic Biol Med 23:1055–1066

    Article  PubMed  CAS  Google Scholar 

  35. Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74:199–205

    Article  PubMed  CAS  Google Scholar 

  36. Bishop GM, Robinson SR, Liu Q, Perry G, Atwood CS, Smith MA (2002) Iron: a pathological mediator of Alzheimer disease? Dev Neurosci 24:184–187

    Article  PubMed  CAS  Google Scholar 

  37. Castellani RJ, Smith MA, Nunomura A, Harris PL, Perry G (1999) Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin? Free Radic Biol Med 26:1508–1512

    Article  PubMed  CAS  Google Scholar 

  38. Yagami T, Ueda K, Sakaeda T, Itoh N, Sakaguchi G, Okamura N, Hori Y, Fujimoto M (2004) Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death. Biochem Pharmacol 67:1153–1165

    Article  PubMed  CAS  Google Scholar 

  39. Zapater P, Moreno J, Horga JF (1997) Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia. Brain Res 772:57–62

    Article  PubMed  CAS  Google Scholar 

  40. Rinkel GJ, Feigin VL, Algra A, Van den Bergh WM, Vermeulen M, van Gijn J (2005) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst. Rev.: CD000277

  41. Robinson MJ, Teasdale GM (1990) Calcium antagonists in the management of subarachnoid haemorrhage. Cerebrovasc Brain Metab Rev 2:205–226

    PubMed  CAS  Google Scholar 

  42. Wadworth AN, McTavish D (1992) Nimodipine. A review of its pharmacological properties, and therapeutic efficacy in cerebral disorders. Drugs Aging 2:262–286

    PubMed  CAS  Google Scholar 

  43. Hakim AM, Evans AC, Berger L, Kuwabara H, Worsley K, Marchal G, Biel C, Pokrupa R, Diksic M, Meyer E (1989) The effect of nimodipine on the evolution of human cerebral infarction studied by PET. J Cereb Blood Flow Metab 9:523–534

    PubMed  CAS  Google Scholar 

  44. Kajikawa H, Ohta T, Yoshikawa Y, Funatsu N, Yamamoto M, Someda K (1979) Cerebral vasospasm and hemoglobins - clinical and experimental studies. Neurol Med Chir (Tokyo) 19:61–71

    Article  CAS  Google Scholar 

  45. Gutteridge JM (1987) The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917:219–223

    PubMed  CAS  Google Scholar 

  46. Regan RF, Panter SS (1993) Neurotoxicity of hemoglobin in cortical cell culture. Neurosci Lett 153:219–222

    Article  PubMed  CAS  Google Scholar 

  47. Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH (1999) Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ Res 84:1302–1309

    PubMed  CAS  Google Scholar 

  48. Mwanjewe J, Hui BK, Coughlin MD, Grover AK. (2001) Treatment of PC12 cells with nerve growth factor increases iron uptake. Biochem J 357:881–886

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas, 79106, USA

    Julie A. Gaasch & Paul R. Lockman

  2. Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, 4209 State Route 44, Rootstown, OH, 44272-9698, USA

    Werner J. Geldenhuys, David D. Allen & Cornelis J. Van der Schyf

  3. Department of Pharmaceutical Chemistry, North-West University, Potchefstroom, 2520, South Africa

    Cornelis J. Van der Schyf

Authors
  1. Julie A. Gaasch
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  2. Werner J. Geldenhuys
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  3. Paul R. Lockman
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  4. David D. Allen
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  5. Cornelis J. Van der Schyf
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Correspondence to Cornelis J. Van der Schyf.

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Special issue dedicated to Dr. Moussa Youdim.

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Gaasch, J.A., Geldenhuys, W.J., Lockman, P.R. et al. Voltage-gated Calcium Channels Provide an Alternate Route for Iron Uptake in Neuronal Cell Cultures. Neurochem Res 32, 1686–1693 (2007). https://doi.org/10.1007/s11064-007-9313-1

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  • DOI: https://doi.org/10.1007/s11064-007-9313-1

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