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Molecular Pharmacology

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Research ArticleArticle

Heteromeric Canonical Transient Receptor Potential 1 and 4 Channels Play a Critical Role in Epileptiform Burst Firing and Seizure-Induced Neurodegeneration

Kevin D. Phelan, Matthew M. Mock, Oliver Kretz, U. Thaung Shwe, Maxim Kozhemyakin, L. John Greenfield, Alexander Dietrich, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi and Fang Zheng
Molecular Pharmacology March 2012, 81 (3) 384-392; DOI: https://doi.org/10.1124/mol.111.075341
Kevin D. Phelan
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Matthew M. Mock
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Oliver Kretz
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U. Thaung Shwe
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Maxim Kozhemyakin
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L. John Greenfield
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Alexander Dietrich
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Lutz Birnbaumer
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Marc Freichel
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Veit Flockerzi
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Fang Zheng
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Abstract

Canonical transient receptor potential channels (TRPCs) are receptor-operated cation channels that are activated in response to phospholipase C signaling. Although TRPC1 is ubiquitously expressed in the brain, TRPC4 expression is the most restrictive, with the highest expression level limited to the lateral septum. The subunit composition of neuronal TRPC channels remains uncertain because of conflicting data from recombinant expression systems. Here we report that the large depolarizing plateau potential that underlies the epileptiform burst firing induced by metabotropic glutamate receptor agonists in lateral septal neurons was completely abolished in TRPC1/4 double-knockout mice, and was abolished in 74% of lateral septal neurons in TRPC1 knockout mice. Furthermore, neuronal cell death in the lateral septum and the cornu ammonis 1 region of hippocampus after pilocarpine-induced severe seizures was significantly ameliorated in TRPC1/4 double-knockout mice. Our data suggest that both TRPC1 and TRPC4 are essential for an intrinsic membrane conductance mediating the plateau potential in lateral septal neurons, possibly as heteromeric channels. Moreover, excitotoxic neuronal cell death, an underlying process for many neurological diseases, is not mediated merely by ionotropic glutamate receptors but also by heteromeric TRPC channels activated by metabotropic glutamate receptors. TRPC channels could be an unsuspected but critical molecular target for clinical intervention for excitotoxicity.

Footnotes

  • This work was supported by National Institute of Neurological Disorders and Stroke [NS050381, NS047546]; the University of Arkansas for Medical Sciences Tobacco Research Fund; the University of Arkansas for Medical Sciences Hornick Research Award; the Deutsche Forschungsgemeinschaft; and in part by the Intramural Research Program of the National Institute of Health National Institute of Environmental Health Sciences [Z01-ES101684].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.075341.

  • ABBREVIATIONS:

    TRPC
    transient receptor potential channel canonical
    mGluR
    metabotropic glutamate receptor
    I-V
    current-voltage
    ACSF
    artificial cerebrospinal fluid
    PCR
    polymerase chain reaction
    PB
    phosphate buffer
    PBS
    phosphate-buffered saline
    FJC
    Fluoro-Jade C
    CA
    cornu ammonis
    1S,3R-ACPD
    (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
    LY367385
    (S)-(+)-α-amino-4-carboxy-2-methyl-benzeneacetic acid
    SKF96365
    1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl-1H-imidazole
    SE
    status epilepticus
    DLSN
    dorsolateral septal nucleus.

  • Received August 19, 2011.
  • Accepted December 5, 2011.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

TRPC Channels, Epileptiform Burst Firing, and Neurodegeneration

Kevin D. Phelan, Matthew M. Mock, Oliver Kretz, U. Thaung Shwe, Maxim Kozhemyakin, L. John Greenfield, Alexander Dietrich, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi and Fang Zheng
Molecular Pharmacology March 1, 2012, 81 (3) 384-392; DOI: https://doi.org/10.1124/mol.111.075341

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Research ArticleArticle

TRPC Channels, Epileptiform Burst Firing, and Neurodegeneration

Kevin D. Phelan, Matthew M. Mock, Oliver Kretz, U. Thaung Shwe, Maxim Kozhemyakin, L. John Greenfield, Alexander Dietrich, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi and Fang Zheng
Molecular Pharmacology March 1, 2012, 81 (3) 384-392; DOI: https://doi.org/10.1124/mol.111.075341
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