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Molecular Pharmacology

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Research ArticleArticle

Canonical Transient Receptor Channel 5 (TRPC5) and TRPC1/4 Contribute to Seizure and Excitotoxicity by Distinct Cellular Mechanisms

Kevin D. Phelan, U Thaung Shwe, Joel Abramowitz, Hong Wu, Sung W. Rhee, Matthew D. Howell, Paul E. Gottschall, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer and Fang Zheng
Molecular Pharmacology February 2013, 83 (2) 429-438; DOI: https://doi.org/10.1124/mol.112.082271
Kevin D. Phelan
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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U Thaung Shwe
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Joel Abramowitz
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Hong Wu
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Sung W. Rhee
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Matthew D. Howell
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Paul E. Gottschall
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Marc Freichel
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Veit Flockerzi
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Lutz Birnbaumer
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Fang Zheng
Department of Neurobiology and Developmental Sciences (K.D.P.), and Department of Pharmacology and Toxicology (U.T.S., H.W., S.W.R., M.D.H., P.E.G., F.Z.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany (M.F.); Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Germany (V.F.); and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A., L.B.)
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Abstract

Seizures are the manifestation of highly synchronized burst firing of a large population of cortical neurons. Epileptiform bursts with an underlying plateau potential in neurons are a cellular correlate of seizures. Emerging evidence suggests that the plateau potential is mediated by neuronal canonical transient receptor potential (TRPC) channels composed of members of the TRPC1/4/5 subgroup. We previously showed that TRPC1/4 double-knockout (DKO) mice lack epileptiform bursting in lateral septal neurons and exhibit reduced seizure-induced neuronal cell death, but surprisingly have unaltered pilocarpine-induced seizures. Here, we report that TRPC5 knockout (KO) mice exhibit both significantly reduced seizures and minimal seizure-induced neuronal cell death in the hippocampus. Interestingly, epileptiform bursting induced by agonists for metabotropic glutamate receptors in the hippocampal CA1 area is unaltered in TRPC5 KO mice, but is abolished in TRPC1 KO and TRPC1/4 DKO mice. In contrast, long-term potentiation is greatly reduced in TRPC5 KO mice, but is normal in TRPC1 KO and TRPC1/4 DKO mice. The distinct changes from these knockouts suggest that TRPC5 and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Furthermore, the reduced seizure and excitotoxicity and normal spatial learning exhibited in TRPC5 KO mice suggest that TRPC5 is a promising novel molecular target for new therapy.

Footnotes

  • This work was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS050381 and NS047546]; the University of Arkansas for Medical Sciences Tobacco Research Fund; and the University of Arkansas for Medical Sciences Hornick Research Award; and also was supported in part by the Intramural Research Program of the National Institutes of Health [Grant Z01-ES 101684].

  • dx.doi.org/10.1124/mol.112.082271.

  • Received September 7, 2012.
  • Accepted November 26, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Research ArticleArticle

Distinct Functional Roles of TRPC5 and TRPC1/4 Channels

Kevin D. Phelan, U Thaung Shwe, Joel Abramowitz, Hong Wu, Sung W. Rhee, Matthew D. Howell, Paul E. Gottschall, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer and Fang Zheng
Molecular Pharmacology February 1, 2013, 83 (2) 429-438; DOI: https://doi.org/10.1124/mol.112.082271

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Research ArticleArticle

Distinct Functional Roles of TRPC5 and TRPC1/4 Channels

Kevin D. Phelan, U Thaung Shwe, Joel Abramowitz, Hong Wu, Sung W. Rhee, Matthew D. Howell, Paul E. Gottschall, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer and Fang Zheng
Molecular Pharmacology February 1, 2013, 83 (2) 429-438; DOI: https://doi.org/10.1124/mol.112.082271
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