Leukemia inhibitory factor (LIF), a cardiac hypertrophic cytokine, increases L-type Ca (2+) current W L) 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(F759/759) 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 I-CaL,L 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%, it = 15, p < 0.05, respectively), but not in gp130(F759/F759) (+9.4%, = 16, N S, 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 2 1, p < 0.05, respectively), but not in gp 130(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, [Ca2+](i) transient and APD. (c) 2007 Elsevier Inc. All rights reserved.