Leukemia inhibitory factor activates cardiac L-type Ca2+ channels via phosphorylation of serine 1829 in the rabbit Cav1.2 subunit

Eiichi Takahashi, Keiichi Fukuda, Shunichiro Miyoshi, Mitsushige Murata, Takahiro Kato, Makoto Ita, Tsutomu Tanabe, Satoshi Ogawa

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29 Citations (Scopus)


We have previously reported that leukemia inhibitory factor (LIF) gradually increased cardiac L-type Ca2+ channel current (I CaL), which peaked at 15 minutes in both adult and neonatal rat cardiomyocytes, and this increase was blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. This study investigated the molecular basis of LIF-induced augmentation of ICaL in rodent cardiomyocytes. LIF induced phosphorylation of a serine residue in the α1c subunit (Cav1.2) of L-type Ca2+ channels in cultured rat cardiomyocytes, and this phosphorylation was inhibited by PD98059. When constructs encoding either a wild-type or a carboxyl-terminal-truncated rabbit Cav1.2 subunit were transfected into HEK293 cells, LIF induced phosphorylation of the resultant wild-type protein but not the mutant protein. Cotransfection of constitutively active mitogen-activated protein kinase kinase also resulted in phosphorylation of the Cav1.2 subunit in the absence of LIF stimulation. In in-gel kinase assays, extracellular signal-regulated kinase phosphorylated a glutathione S-transferase fusion protein of the carboxyl-terminal region of Cav1.2 (residues 1700 through 1923), which contains the consensus sequence Pro-Leu-Ser-Pro. A point mutation within this consensus sequence, which results in a substitution of alanine for serine at residue 1829 (S1829A), was sufficient to abolish the LIF-induced phosphorylation. LIF increased ICaL in HEK cells transfected with wild-type Cav1.2 but not with the mutated version. These results provide direct evidence that LIF phosphorylates the sefine residue at position 1829 of the Cav1.2 subunit via the actions of extracellular signal-regulated kinase and that this phosphorylation increases ICaL in cardiomyocytes.

Original languageEnglish
Pages (from-to)1242-1248
Number of pages7
JournalCirculation research
Issue number9
Publication statusPublished - 2004 May 14
Externally publishedYes


  • Cardiomyocytes
  • Extracellular signal-regulated kinase
  • L-type Ca channels
  • Leukemia inhibitory factor
  • Phosphorylation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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