title: SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent I CaL, [Ca2+]i transient, and APD increase in cardiomyocytes.
abstract: Leukemia inhibitory factor (LIF), a cardiac hypertrophic cytokine, increases L-type Ca(2+) current (I(CaL)) via ERK-dependent and PKA-independent phosphorylation of serine 1829 in the Cav(1.2) 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 (gp130(F759/F759) group), and wild-type mice (WT group) were used. A whole-cell patch clamp experiment was performed, and intracellular Ca(2+) concentration ([Ca(2+)](i) transient) was monitored. The I(CaL) density and [Ca(2+)](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 I(CaL) density significantly in WT (+27.0%, n=16 p<0.05, and +32.2%, n=15, p<0.05, respectively), but not in gp130(F759/F759) (+9.4%, n=16, NS, and -6.1%, n=13, NS, respectively). Administration of LIF and IL-6+sIL-6r increased [Ca(2+)](i) transient significantly in WT (+18.8%, n=13, p<0.05, and +32.0%, n=21, p<0.05, respectively), but not in gp130(F759/F759) (-3.8%, n=7, NS, and -6.4%, n=10, NS, respectively). LIF prolonged APD(80) significantly in WT (10.5+/-4.3%, n=12, p<0.05), but not in gp130(F759/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 I(CaL), [Ca(2+)](i) transient and APD.
authors.affiliation: Division of Cardiology, Department of Medicine, Keio University School of Medicine, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Ikegami
authors.forename: Kojiro
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Murata
authors.forename: Eiichi
authors.initials: E
authors.lastname: Takahashi
authors.forename: Kouji
authors.initials: K
authors.lastname: Shimoda
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.forename: Hideo
authors.initials: H
authors.lastname: Mitamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D005419:Flavonoids; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D050822:Cytokine Receptor gp130; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one