SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent ICaL, [Ca2+]i transient, and APD increase in cardiomyocytes

Yoko Hagiwara, Shunichiro Miyoshi, Keiichi Fukuda, Nobuhiro Nishiyama, Yukinori Ikegami, Kojiro Tanimoto, Mitsushige Murata, Eiichi Takahashi, Kouji Shimoda, Toshio Hirano, Hideo Mitamura, Satoshi Ogawa

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Abstract

Leukemia inhibitory factor (LIF), a cardiac hypertrophic cytokine, increases L-type Ca2+ current (ICaL) via ERK-dependent and PKA-independent phosphorylation of serine 1829 in the Cav1.2 subunit. The signaling cascade through gp130 is involved in this augmentation. However, there are two major cascades downstream of gp130, i.e. JAK/STAT3 and SHP2/ERK. In this study, we attempted to clarify which of these two cascades plays a more important role. Knock-in mouse line, in which the SHP2 signal was disrupted (gp130F759/F759 group), and wild-type mice (WT group) were used. A whole-cell patch clamp experiment was performed, and intracellular Ca2+ concentration ([Ca2+]i transient) was monitored. The ICaL density and [Ca2+]i transient were measured from the untreated cells and the cells treated with LIF or IL-6 and soluble IL-6 receptor (IL-6 + sIL-6r). Action potential duration (APD) was also recorded from the ventricle of each mouse, with or without LIF. Both LIF and IL-6 + sIL-6r increased ICaL density significantly in WT (+ 27.0%, n = 16 p < 0.05, and + 32.2%, n = 15, p < 0.05, respectively), but not in gp130F759/F759 (+ 9.4%, n = 16, NS, and - 6.1%, n = 13, NS, respectively). Administration of LIF and IL-6 + sIL-6r increased [Ca2+]i transient significantly in WT (+ 18.8%, n = 13, p < 0.05, and + 32.0%, n = 21, p < 0.05, respectively), but not in gp130F759/F759 (- 3.8%, n = 7, NS, and - 6.4%, n = 10, NS, respectively). LIF prolonged APD80 significantly in WT (10.5 ± 4.3%, n = 12, p < 0.05), but not in gp130F759/F759 (- 2.1 ± 11.2%, n = 7, NS). SHP2-mediated signaling cascade is essential for the LIF and IL-6 + sIL-6r-dependent increase in ICaL, [Ca2+]i transient and APD.

Original languageEnglish
Pages (from-to)710-716
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume43
Issue number6
DOIs
Publication statusPublished - 2007 Dec 1

Keywords

  • Fluo-4
  • IL-6
  • Ion channel
  • L-type Ca current
  • Leukemia inhibitory factor (LIF)
  • Patch clamp
  • SHP2

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Hagiwara, Y., Miyoshi, S., Fukuda, K., Nishiyama, N., Ikegami, Y., Tanimoto, K., Murata, M., Takahashi, E., Shimoda, K., Hirano, T., Mitamura, H., & Ogawa, S. (2007). SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent ICaL, [Ca2+]i transient, and APD increase in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 43(6), 710-716. https://doi.org/10.1016/j.yjmcc.2007.09.004