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

该项目是为了研究心肌细胞中的T型Ca^<2+>通道，尤其是在finotrial节点中，与Pacemaker活性有关^<2+>通道和心脏自动化：在孤立的豚鼠促鼻涕节点中记录了动作电位和膜，以及PGF_ <2α>和TXA_2的阳性时体作用的离子机制证明TXA_2增加了孤立的Sinotrial节点细胞的自发发射频率，即这种增加是由T型Ca^<2+>通道的激活引起的。在肺动脉高压症中，L型^<2+>通道的PGF_<2α>的阳性年度重塑被注入…更多的单蛋白，肺部和右心房肥大的肺部。在单核治疗的大鼠中，伴随着L型Ca^<2+>亚基和辅助B_2亚基的mRNA表达的明显重新表达，而B_3亚基的增加。与对照大鼠的右心房细胞相比，v3.1和Cav3.2的蛋白质水平与CAV3.1亚基的蛋白质水平相比。 ca^<2+>右心房Ls.3）电压依赖性Ca^<2+>通道的功能分析，从Syminal中释放。 Ca^ <2+>的辅助β_3亚基与α1b亚基相关联，形成N型Ca^ <2+>通道，因此预计将在刺激的诱发甲肾上腺素的释放中发挥作用），和遗嘱型（WT）小鼠，以研究Cavβ_3在体内交感评论中的可能作用，并阐明Cavβ_3在调节神经aling中的功能作用。4）TRP通道蛋白的功能分析Ca^<2+的重要性Ca^<2+ >在心脏肥大反应中的进入，我们证明了TRPC1作为心脏PHY的功能性想象者。