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 language | English |
|---|---|
| Pages (from-to) | 710-716 |
| Number of pages | 7 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 43 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2007 Dec |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=36448956446&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36448956446&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2007.09.004
DO - 10.1016/j.yjmcc.2007.09.004
M3 - Article
VL - 43
SP - 710
EP - 716
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 6
ER -