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Molecular Pharmacology

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Research ArticleArticle

Destabilization of Nav1.7 Sodium Channel α-Subunit mRNA by Constitutive Phosphorylation of Extracellular Signal-Regulated Kinase: Negative Regulation of Steady-State Level of Cell Surface Functional Sodium Channels in Adrenal Chromaffin Cells

Toshihiko Yanagita, Hideyuki Kobayashi, Yasuhito Uezono, Hiroki Yokoo, Takashi Sugano, Tomokazu Saitoh, Shin-Ichi Minami, Seiji Shiraishi and Akihiko Wada
Molecular Pharmacology May 2003, 63 (5) 1125-1136; DOI: https://doi.org/10.1124/mol.63.5.1125
Toshihiko Yanagita
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Hideyuki Kobayashi
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Yasuhito Uezono
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Hiroki Yokoo
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Takashi Sugano
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Tomokazu Saitoh
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Shin-Ichi Minami
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Seiji Shiraishi
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Akihiko Wada
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Abstract

In cultured bovine adrenal chromaffin cells expressing Nav1.7 isoform of voltage-dependent Na+channels, treatment (≥6 h) with serum deprivation, PD98059, or U0126 increased cell surface [3H]saxitoxin ([3H]STX) binding by ∼58% (t1/2 = 12.5 h), with no change in the Kd value. Immunoblot analysis showed that either treatment attenuated constitutive phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2 but not of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) 1 and JNK2. The increase of [3H]STX binding and the attenuated phosphorylation of ERK1 and ERK2 returned to the control nontreated levels after the addition of serum or the washout of PD98059- or U0126-treated cells. Simultaneous treatment of serum deprivation with PD98059 or U0126 did not produce an additional increasing effect on [3H]STX binding, compared with either treatment alone. In cells subjected to either treatment, veratridine-induced maximum 22Na+ influx was augmented by ∼47%, with no change in the EC50 value;Ptychodiscus brevis toxin-3 enhanced veratridine-induced22Na+ influx by 2-fold, as in nontreated cells. Serum deprivation, PD98059, or U0126 increased Na+ channel α- but not β1- subunit mRNA level by ∼50% between 3 and 24 h; cycloheximide, an inhibitor of protein synthesis, increased α-subunit mRNA level and nullified additional increasing effect of either treatment on α-subunit mRNA level. Either treatment prolonged half-life of α-subunit mRNA from 17.5 to ∼26.3 h without altering α-subunit gene transcription. Thus, constitutively phosphorylated/activated ERK destabilizes Na+ channel α-subunit mRNA via translational event, which negatively regulates steady-state level of α-subunit mRNA and cell surface expression of functional Na+ channels.

Footnotes

  • This research was supported by a grant from the Ichiro Kanehara Foundation, and by a Grant-in-Aid for 21st century COE (Centers of Excellence) Program (Life Science) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

  • Abbreviations:
    DRG
    dorsal root ganglion
    APP
    amyloid precursor protein
    BAPTA-AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester
    DMSO
    dimethyl sulfoxide
    ERK
    extracellular signal-regulated kinase
    FRAP
    FK506 binding protein- and rapamycin-associated protein
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    hNE-Na
    human neuroendocrine type Na+channel α-subunit
    JNK
    c-Jun N-terminal kinase
    kb
    kilobase(s)
    KRP
    Krebs-Ringer phosphate
    MAPK
    mitogen-activated protein kinases
    MEK
    MAPK/ERK kinase
    nt
    nucleotides
    p38
    p38 mitogen-activated protein kinase
    pBII
    plasmid Bluescript II
    PbTx-3
    Ptychodiscus brevis toxin-3
    PKC
    protein kinase C
    RTK
    receptor tyrosine kinase
    SSC
    saline-sodium citrate
    STX
    saxitoxin
    TTX
    tetrodotoxin
    PD98059
    2′-amino-3′-methoxyflavone
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    SP600125
    anthra[19-cd]pyrazol-6(2H)-one
    U0126
    14-diamino-23-dicyano-14-bis(2-aminophenylthio)butadiene
    A23187
    calcimycin
    • Received August 7, 2002.
    • Accepted January 23, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Destabilization of Nav1.7 Sodium Channel α-Subunit mRNA by Constitutive Phosphorylation of Extracellular Signal-Regulated Kinase: Negative Regulation of Steady-State Level of Cell Surface Functional Sodium Channels in Adrenal Chromaffin Cells

Toshihiko Yanagita, Hideyuki Kobayashi, Yasuhito Uezono, Hiroki Yokoo, Takashi Sugano, Tomokazu Saitoh, Shin-Ichi Minami, Seiji Shiraishi and Akihiko Wada
Molecular Pharmacology May 1, 2003, 63 (5) 1125-1136; DOI: https://doi.org/10.1124/mol.63.5.1125

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Research ArticleArticle

Destabilization of Nav1.7 Sodium Channel α-Subunit mRNA by Constitutive Phosphorylation of Extracellular Signal-Regulated Kinase: Negative Regulation of Steady-State Level of Cell Surface Functional Sodium Channels in Adrenal Chromaffin Cells

Toshihiko Yanagita, Hideyuki Kobayashi, Yasuhito Uezono, Hiroki Yokoo, Takashi Sugano, Tomokazu Saitoh, Shin-Ichi Minami, Seiji Shiraishi and Akihiko Wada
Molecular Pharmacology May 1, 2003, 63 (5) 1125-1136; DOI: https://doi.org/10.1124/mol.63.5.1125
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