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

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Leukemia Inhibitory Factor
Cardiac Myocytes
Action Potentials
Interleukin-6
Interleukin-6 Receptors
Serine
Phosphorylation
Cytokines

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

Cite this

SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent ICaL, [Ca2+]i transient, and APD increase in cardiomyocytes. / Hagiwara, Yoko; Miyoshi, Shunichiro; Fukuda, Keiichi; Nishiyama, Nobuhiro; Ikegami, Yukinori; Tanimoto, Kojiro; Murata, Mitsushige; Takahashi, Eiichi; Shimoda, Kouji; Hirano, Toshio; Mitamura, Hideo; Ogawa, Satoshi.

In: Journal of Molecular and Cellular Cardiology, Vol. 43, No. 6, 12.2007, p. 710-716.

Research output: Contribution to journalArticle

Hagiwara, Yoko ; Miyoshi, Shunichiro ; Fukuda, Keiichi ; Nishiyama, Nobuhiro ; Ikegami, Yukinori ; Tanimoto, Kojiro ; Murata, Mitsushige ; Takahashi, Eiichi ; Shimoda, Kouji ; Hirano, Toshio ; Mitamura, Hideo ; Ogawa, Satoshi. / SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent ICaL, [Ca2+]i transient, and APD increase in cardiomyocytes. In: Journal of Molecular and Cellular Cardiology. 2007 ; Vol. 43, No. 6. pp. 710-716.
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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.",
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T1 - SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent ICaL, [Ca2+]i transient, and APD increase in cardiomyocytes

AU - Hagiwara, Yoko

AU - Miyoshi, Shunichiro

AU - Fukuda, Keiichi

AU - Nishiyama, Nobuhiro

AU - Ikegami, Yukinori

AU - Tanimoto, Kojiro

AU - Murata, Mitsushige

AU - Takahashi, Eiichi

AU - Shimoda, Kouji

AU - Hirano, Toshio

AU - Mitamura, Hideo

AU - Ogawa, Satoshi

PY - 2007/12

Y1 - 2007/12

N2 - 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.

AB - 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.

KW - Fluo-4

KW - IL-6

KW - Ion channel

KW - L-type Ca current

KW - Leukemia inhibitory factor (LIF)

KW - Patch clamp

KW - SHP2

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U2 - 10.1016/j.yjmcc.2007.09.004

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