Novel Therapeutic Strategy for Heart Failure : Molecular Mechanism underlying the Regulation of Ca^<2+> Signaling in the Heart

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1) Treatment with H_2O_2 activates G_I/G_o in rat neonatal ventricular myocytes. We found that H_2O_2 modifies Cys^<287> and Cys^<326> of G_<αi>. Angiotensin II stimulation generated ROS and induced the activation of MAP kinase. The elimination of ROS by the co expression of peroxiredoxn II abolished JNK activation induced by angiotensin II without affecting ERK or p38 MAPK activities. These results indicate that ROS, produced by receptor stimulation, serves as an intracellular mediator linking the receptor stimulation and the activation of MARK (JNK).2) Aiming at elucidating the molecular mechanism underlying the gating modulation of L-type Ca^<2+> channels by Ca^<2+> channel modulators, we searched for the DHP binding sites in L-type Ca^<2+> channel a_<1C> subunit. We identified the two key residues, Phe^<1112> and Ser^<1115> in IIIS5-S6 pore-forming region. The double mutant Ca^<2+> channel (F1112A/S115A) was insensitive to Ca^<2+> channel agonists, and weakly blocked by both Ca^<2+ … More > channel agonists and antagonists. We proposed a novel model for the modulation of Ca^<2+> channel gating by the binding of Ca^<2+> channel modulators at the pore-forming region of Ca^<2+> channel α_<1C> subunit.3) We investigated the physiological role of the privileged cross-communication between L-type Ca^<2+> channels and ryanodine receptors. We found that Ca^<2+> channels function as a sensor to the SR Ca^<2+> content to manipulate APD and the total Ca^<2+> influx through Ca^<2+> channels during APs, via the Ca^<2+>-dependent inactivation of Ca^<2+> channels produced by proximal Ca^<2+>-induced Ca^<2+> release CICR-dependent CDI, to ensure the efficacy of CICR.4) In order to elucidate the physiological role of Na^+-Ca^<2+> exchanger (NCX) in cardiac excitation-contraction coupling, we examined the Ca^<2+> signaling in NCX knockout heterozygous mouse heart. We found that the forward mode NCX activity plays a physiologically important role in the regulation of the SR Ca^<2+> content. Less