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

T型Ca^<2>通道生物活性物质的调节及其对心脏自律性调节的贡献

基本信息

批准号：
18590201
负责人：
ONO Kyoichi
金额：
$ 2.52万
依托单位：
Akita University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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

本研究旨在探讨T型Ca^<2+>通道在心肌细胞中的功能作用，特别是在窦房结起搏细胞中，其可能对起搏活动的贡献。获得以下结果：1）T型Ca^<2+>通道与心脏自律性：采用膜片钳方法记录了离体豚鼠窦房结细胞的动作电位和膜电流，探讨了PGF_<2α>和TXA_2正性变时作用的离子机制。我们证明PGF_2α和TXA_2均能增加离体窦房结细胞的自发放电频率，这种增加是通过激活T型Ca^<2+>通道引起的。结果提示T型Ca^<2+>通道在PGF_（2α）和TXA_2的正性变时作用中起重要作用。2）肺动脉高压时L型和T型Ca^<2+>通道的电重构 ...更多信息野百合碱，导致肺动脉高压伴右心房和心室肥大。结果表明，野百合碱处理的大鼠右心房细胞L型Ca ^<2 +>通道电流密度显著降低，CaV 1.2亚基和辅助B2亚基mRNA表达显著减少，B3亚基mRNA表达显著增加。另一方面，野百合碱处理组大鼠右心房细胞的T型Ca^<2+>电流较对照组明显。CaV3.1和CaV3.2的mRNA表达水平或CaV3.1亚基的蛋白水平没有观察到显著差异。这些结果表明，肺动脉高压导致右心房肥大，并与右心房细胞Ca^<2+>通道的电生理分子特性改变有关。3）电压依赖性Ca^<2+>通道的功能分析交感神经末梢释放去甲肾上腺素依赖于神经元电压门控N型Ca^<2 +>通道的Ca^<2+内流。Ca^<2+>通道的辅助β 3亚基（Cavβ 3）优先与α1B亚基结合形成N型Ca^<2+>通道，并在刺激诱发的去甲肾上腺素释放中发挥作用。我们采用Cavβ_3-null，Cavβ_3-overexpression，（Cavβ_3-Tg）和野生型（WT）小鼠，探讨Cav β_3在交感神经对心率调节中的可能作用，阐明Cavβ_3在交感神经信号转导中的功能作用。4）TRP通道蛋白的功能分析Ca^<2+>内流在心肌肥厚反应中的重要性已被充分证实，但实际的Ca^2+进入通道仍然未知。我们证明TRPC 1是心脏肥大的重要功能调节因子。我们还发现TRPC 1在血管平滑肌细胞肥大的发展中起着重要作用。