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
N1 - Funding Information:
This work was supported by the Suntory Fund for Advanced Cardiac Therapeutics, Keio University School of Medicine. The transgenic mouse was kindly provided from Dr. Takuya Ohtani, Osaka University School of Medicine.
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
DO - 10.1016/j.yjmcc.2007.09.004
M3 - Article
C2 - 17961593
AN - SCOPUS:36448956446
SN - 0022-2828
VL - 43
SP - 710
EP - 716
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -