Modulation of NMDAR subunit expression by TRPM2 channels regulates neuronal vulnerability to ischemic cell death.

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  • Author(s): Alim I;Alim I; Teves L; Li R; Mori Y; Tymianski M
  • Source:
    The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2013 Oct 30; Vol. 33 (44), pp. 17264-77.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE
    • Publication Information:
      Publication: Washington, DC : Society for Neuroscience
      Original Publication: [Baltimore, Md.] : The Society, c1981-
    • Subject Terms:
      Brain Ischemia/*metabolism ; Brain Ischemia/*prevention & control ; Down-Regulation/*genetics ; Neurons/*metabolism ; Protein Subunits/*genetics ; Receptors, N-Methyl-D-Aspartate/*genetics ; TRPM Cation Channels/*physiology; Animals ; Brain Ischemia/pathology ; Cell Death/physiology ; Cell Survival/physiology ; Cells, Cultured ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neural Pathways/physiology ; Neurons/pathology ; Protein Subunits/biosynthesis ; Receptors, N-Methyl-D-Aspartate/biosynthesis
    • Abstract:
      Neuronal vulnerability to ischemia is dependent on the balance between prosurvival and prodeath cellular signaling. In the latter, it is increasingly appreciated that toxic Ca(2+) influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a nonspecific cation channel having homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca(2+) influx has been difficult to study because of the lack of specific modulators. Here we used TRPM2-null mice (TRPM2(-/-)) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2(-/-) mice subjected to transient middle cerebral artery occlusion exhibited smaller infarcts when compared with wild-type animals, suggesting that the absence of TRPM2 is neuroprotective. Surprisingly, field potentials (fEPSPs) recorded during redox modulation in brain slices taken from TRPM2(-/-) mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas wild-type fEPSPs were unaffected. The upregulation in fEPSP in TRPM2(-/-) neurons was blocked selectively by a GluN2A antagonist. This increase in excitability of TRPM2(-/-) fEPSPs during redox modulation depended on the upregulation and downregulation of GluN2A- and GluN2B-containing NMDARs, respectively, and on augmented prosurvival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor GSK3β. Our results suggest that TRPM2 plays a role in downregulating prosurvival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage.
    • References:
      Nat Med. 2008 Jul;14(7):738-47. (PMID: 18542050)
      Free Radic Biol Med. 1989;7(1):3-8. (PMID: 2546869)
      Bioorg Med Chem Lett. 2002 Apr 8;12(7):1099-102. (PMID: 11909726)
      Am J Physiol Cell Physiol. 2004 Jan;286(1):C129-37. (PMID: 14512294)
      J Neurosci. 2004 Nov 10;24(45):10248-59. (PMID: 15537897)
      J Neurochem. 2005 Aug;94(3):713-22. (PMID: 16000165)
      Channels (Austin). 2009 Jan-Feb;3(1):12-5. (PMID: 19221512)
      J Neurosci. 2000 Sep 1;20(17):6340-6. (PMID: 10964939)
      Sci Signal. 2009 May 19;2(71):ra23. (PMID: 19454650)
      J Pharmacol Sci. 2006 May;101(1):66-76. (PMID: 16651700)
      Lancet Neurol. 2002 Oct;1(6):383-6. (PMID: 12849400)
      Nat Rev Neurosci. 2010 Oct;11(10):682-96. (PMID: 20842175)
      J Cereb Blood Flow Metab. 1997 Apr;17(4):455-63. (PMID: 9143228)
      J Physiol. 2009 Mar 1;587(Pt 5):965-79. (PMID: 19124544)
      J Cereb Blood Flow Metab. 1993 Jan;13(1):125-34. (PMID: 8417001)
      Lancet. 2000 Jun 3;355(9219):1949-54. (PMID: 10859040)
      Cell Mol Life Sci. 2004 Mar;61(6):657-68. (PMID: 15052409)
      Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9854-9. (PMID: 19482936)
      Stroke. 1986 May-Jun;17(3):472-6. (PMID: 3715945)
      J Pharmacol Exp Ther. 2010 Dec;335(3):636-44. (PMID: 20810618)
      Nature. 1993 Jan 7;361(6407):31-9. (PMID: 8421494)
      Cardiovasc Drug Rev. 2007 Spring;25(1):61-75. (PMID: 17445088)
      Neurotoxicology. 2010 Mar;31(2):204-14. (PMID: 20064552)
      J Biol Chem. 2000 Nov 3;275(44):34266-71. (PMID: 10954722)
      Nature. 2001 May 31;411(6837):590-5. (PMID: 11385574)
      Nat Neurosci. 2011 Oct 26;14(11):1369-73. (PMID: 22030547)
      Trends Pharmacol Sci. 2008 May;29(5):268-75. (PMID: 18384889)
      Stroke. 2004 Jul;35(7):1720-5. (PMID: 15155973)
      Pflugers Arch. 2010 Jul;460(2):525-42. (PMID: 20229265)
      J Neurosci. 2003 Jan 1;23(1):269-76. (PMID: 12514224)
      Nat Neurosci. 2009 Oct;12(10):1300-7. (PMID: 19734892)
      J Cereb Blood Flow Metab. 2011 Nov;31(11):2160-8. (PMID: 21587268)
      Neuron. 1994 Mar;12(3):529-40. (PMID: 7512349)
      J Neurosci. 2006 Apr 26;26(17):4509-18. (PMID: 16641230)
      Science. 2002 Oct 25;298(5594):846-50. (PMID: 12399596)
      J Neurosci Res. 2008 Nov 15;86(15):3322-30. (PMID: 18646208)
      Stroke. 2008 Nov;39(11):3042-8. (PMID: 18688011)
      J Neurosci. 2008 Oct 15;28(42):10696-710. (PMID: 18923045)
      J Neurochem. 1997 Feb;68(2):469-78. (PMID: 9003031)
      J Cereb Blood Flow Metab. 2010 Aug;30(8):1441-9. (PMID: 20145658)
      J Neurosci. 2012 Mar 14;32(11):3931-41. (PMID: 22423113)
      J Biol Chem. 2005 Feb 18;280(7):6138-48. (PMID: 15561722)
      Science. 1999 Jun 11;284(5421):1845-8. (PMID: 10364559)
      Nat Neurosci. 2001 Jun;4(6):565-6. (PMID: 11369935)
      J Neurosci. 2006 Mar 15;26(11):2956-63. (PMID: 16540573)
      J Cereb Blood Flow Metab. 2007 Jan;27(1):135-41. (PMID: 16736049)
      Nat Protoc. 2006;1(4):2075-81. (PMID: 17487197)
      J Neurochem. 2005 Nov;95(3):756-70. (PMID: 16248887)
      Mol Cell. 2002 Jan;9(1):163-73. (PMID: 11804595)
      Lancet. 1997 Jan 4;349(9044):32. (PMID: 8999265)
      Mol Cell Neurosci. 2003 Feb;22(2):202-9. (PMID: 12676530)
      J Neurosci. 2005 Apr 27;25(17):4279-87. (PMID: 15858054)
      Biochem Soc Trans. 2006 Nov;34(Pt 5):936-8. (PMID: 17052231)
      J Neurosci. 2000 Apr 1;20(7):2567-74. (PMID: 10729337)
      J Neurosci. 2004 Nov 3;24(44):9993-10002. (PMID: 15525785)
      J Neurosci. 2007 Mar 14;27(11):2846-57. (PMID: 17360906)
      Eur J Neurosci. 2001 Dec;14(11):1809-19. (PMID: 11860476)
      Neuropharmacology. 2005 Mar;48(3):354-9. (PMID: 15721167)
      Trends Neurosci. 2003 Feb;26(2):81-9. (PMID: 12536131)
      Mol Brain. 2011 Dec 21;4:44. (PMID: 22188973)
      Cell. 2003 Dec 26;115(7):863-77. (PMID: 14697204)
      Pflugers Arch. 2005 Oct;451(1):243-9. (PMID: 16044308)
      Science. 2004 May 14;304(5673):1021-4. (PMID: 15143284)
      Stroke. 1996 Jun;27(6):1124-9. (PMID: 8650725)
    • Grant Information:
      MOP89720 Canada Canadian Institutes of Health Research
    • Accession Number:
      0 (Protein Subunits)
      0 (Receptors, N-Methyl-D-Aspartate)
      0 (TRPM Cation Channels)
      0 (TRPM2 protein, mouse)
    • Publication Date:
      Date Created: 20131101 Date Completed: 20131223 Latest Revision: 20220309
    • Publication Date:
      20240829
    • Accession Number:
      PMC6618359
    • Accession Number:
      10.1523/JNEUROSCI.1729-13.2013
    • Accession Number:
      24174660