Study on regulatory mechanism for cardiac contraction : seeking for therapeutic basis of heart failure.

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The aim of this project was to open up a novel concept for therapeutic basis of heart failure. In the past three years from 1998 through 2000, we have carried out the research project by focusing on Ca^<2+> signaling in cardiac E-C coupling at the early stage of heart failure, molecular basis for cardiac protection against ischemia, molecular mechanism underlying modulation of L-type Ca^<2+> channel gating, cellular mechanism for desensitization of β adrenergic receptors. Our research products are summarized as follows :1) With respect to the molecular basis for cardiac protection against ischemia, we found that ROS (reactive oxygen species) directly activates Gi and Go, which results in the activation of ERK (extracellular signal-regulated kinase). We opened up a novel concept that ROS is also involved in the signal transduction pathway leading to cardiac protection. 2) We identified Ser1115 in the pore domain of L-type Ca^<2+> channel α_<1C> subunit as the critical determinant for modulation of L-type Ca^<2+> channel gating by Ca^<2+> channel agonists by comparing the amino acid sequences between DHP-sensitive mammalian α_<1C> subunit and DHP-insensitive Ca^<2+> channel α_1 subunit of sea animals. Our finding opened up a novel concept in the gating mechanism of voltage-dependent Ca^<2+> channels. We also found that Ser1901 in the carboxy terminal of L-type Ca^<2+> channel α_<1C> subunit is the target for the PKA-modulation. 3) We found that, in the early adaptive stage of heart failure, the Ca^<2+> handling mechanism, especially Na^<+-> Ca^<2+> exchange activity, is up-regulated in ventricular myocytes of coronary artery ligation model rats. 4) We clarified the molecular basis for the tolerance of β_1 adrenergic receptors against internalization on exposure to β adrenergic agonists, which partially explains the reason for the slower rate of down regulation β_1 adrenergic receptors.