PT  - JOURNAL ARTICLE
AU  - Toshihiko Yanagita
AU  - Hideyuki Kobayashi
AU  - Yasuhito Uezono
AU  - Hiroki Yokoo
AU  - Takashi Sugano
AU  - Tomokazu Saitoh
AU  - Shin-Ichi Minami
AU  - Seiji Shiraishi
AU  - Akihiko Wada
TI  - Destabilization of Na<sub>v</sub>1.7 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
AID  - 10.1124/mol.63.5.1125
DP  - 2003 May 01
TA  - Molecular Pharmacology
PG  - 1125--1136
VI  - 63
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/63/5/1125.short
4100  - http://molpharm.aspetjournals.org/content/63/5/1125.full
SO  - Mol Pharmacol2003 May 01; 63
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics