Modulation by bioactive substances of T-type Ca^<2+> channels and their contribution to the regulation of cardiac automaticity

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This project was carried out to investigate the functional role of the T-type Ca^<2+>channel in cardiac myocytes, particularly in pacemaker cells of sinoatrial node in relation to its possible contribution to the pacemaker activity. The following results were obtained.1) T-type Ca^<2+> channel and cardiac automaticity:The action potential and membrane currents were recorded in isolated guinea-pig sinoatrial node cells and the ionic mechanisms underlying the positive chronotropic action of PGF_<2α> and TXA_2 were investigated by the patch clamp method. We demonstrated that both PGF_<2α> and TXA_2 increased the spontaneous firing frequency of isolated sinoatrial node cells, and that this increase was caused by activation of T-type Ca^<2+> channels. The results indicate the functional role of T-type Ca^<2+> channel in the positive chronotropic action of PGF_<2α> and TXA_2.2) Electrical remodeling of L-and T-type Ca^<2+> Channels during pulmonary hypertensionWistar rats were injected with … More monocrotaline, resulting in pulmonary hypertension with right atrial and ventricular hypertrophy. The L-type Ca^<2+> channel current density was significantly decreased in right atrial cells of monocrotaline-treated rats, accompanied by a significant reduction in mRNA expression of the L-type Ca^<2+> channel CaV1.2 subunit and accessory B_2 subunit, and an increase in the B_3 subunit. On the other hand, T-type Ca^<2+> current was more marked in the right atrial cells of monocrotaline-treated rats than in those of control rats. No significant differences were observed in the mRNA expression levels of CaV3.1 and CaV3.2 or the protein level of the CaV3.1 subunit. These results indicate that pulmonary hypertension causes right atrial hypertrophy, associated with alteration of the electrophysiologic molecular properties of Ca^<2+> channels in right atrial cells.3) Functional analysis of voltage-dependent Ca^<2+> channelsNoradrenaline release from sympathetic nerve terminals is dependent on Ca^<2+> entry through neuronal voltage-gated N-type Ca^<2+> channels. The accessory β_3 subunits of Ca^<2+> channels (Cavβ_3) are preferentially associated with α1B subunit to form N-type Ca^<2+> channels, and are therefore expected to play a functional role in the stimulation-evoked release of noradrenaline. We employed Cavβ_3-null, Cavβ_3-overexpresing (Cavβ_3-Tg), and wild type (WT) mice to investigate the possible roles of Cavβ_3 in the sympathetic regulation of heart rate in vivo, and clarified the functional roles of Cavβ_3 in regulating sympathetic nerve signaling.4) Functional analysis of TRP channel proteinsThe importance of Ca^<2+> entry in the cardiac hypertrophic response is well documented, but the actual Ca^<2+> entry channels remained unknown. We demonstrated TRPC1 as a functionally important regulator of cardiac hypertrophy. We also showed that TRPC1 plays an important role in the development of hypertrophy of vascular smooth muscle cells Less