Inward rectification and voltage-dependent activation of HERG K channels

HERG K 通道的内向整流和电压依赖性激活

• 批准号: 08670055
• 负责人: ONO Kyoichi
• 金额: $ 1.41万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670055/
• 关键词: HERG; sinoatrial node; delayd rectifier K current; pacemaker activity; IKr; IKs; 洞房結節; Caイオン

We have demonstrated that the conductance and kinetics of I_K in SA node cells closely resembled those of the rapidly activating component of I_K (I_<Kr>) which is coded by human eag-related gene (HERG), in terms of ion selectivity, gating parameters of activation, inward rectification of the steady-state IV relation, the single channel conductance, and selective blockage by class III antiarrythmic agents. The inward rectifying property was characterized by decrease of open probablity at positive potentials. Under the inside-out mode, the open probabilty did not increase even if the patch membrane was exposed to the solution containing on Mg^<2+> or Ca^<2+>, indicating that the inward rectification is not due to block by these cations but derived from the intirinsic gating of the I_<Kr> channels.When the external Ca^<2+> was removed, the decay of the tail current was markedly prolonged. The effect of external Ca^<2+> was voltage-and concentration-dependent. The results indicate that the gating of I_<Kr>, which has been believed to be an intrinsic voltage-dependent mechanism, might be caused by a time-and voltage-dependent block and unblock of the I_<Kr> channels by external Ca^<2+>.I_<Kr> is essential in maintaining the automaticity of rabbit SAN cells. To extend this hypothesis to other species, we made an attempt to isolate pacemaker cells from porcine hearts. The isolated cells exhibited spontaneous activity with beating rate of approximately 80 min-1 in normal Tyrode solution. It was found that the delayd rectifier K^+ current of porcine SAN cells consisted of the slowly activating delayd rectifier K + current, in contrast to I_<Kr> of rabbit. The different I_K might contribute to different heart rate among various species.

我们证明了窦房结细胞I_K的电导和动力学与人EAG相关基因（HERG）编码的I_K快速激活组分（I_K<Kr>）在离子选择性、激活的门控参数、稳态IV关系的内向整流、单通道电导和III类抗心律失常药物的选择性阻断等方面非常相似。内向整流特性的特点是在正电位下开放概率降低。在由内向外模式下，即使将膜片暴露于含有Mg^&lt;2+&gt;或Ca^&lt;2+&gt;的溶液中，其开放概率也没有增加，表明内向整流不是由于这些阳离子的阻断，而是来自I_2通道的内分泌门控<Kr>，当去除外部Ca^&lt;2+&gt;时，尾电流的衰减明显延长。外源性Ca^&lt;2+&gt;的作用具有电压和浓度依赖性。结果表明，I_2门控<Kr>是一种内在的电压依赖性机制，可能是由外源性Ca ~（2+）对I_2通道的时间和电压依赖性阻滞和解除阻滞而引起<Kr>的，I_2<Kr>是维持家兔SAN细胞自律性的必要条件。为了将这一假设扩展到其他物种，我们尝试从猪心脏中分离起搏细胞。分离的细胞在正常台氏液中表现出自发活动，搏动率约为80 min-1。结果表明，猪窦房结细胞的延迟整流钾电流由慢激活的延迟整流钾电流组成，而兔窦房结细胞的延迟整流钾电流则由慢激活的延迟整流钾电流组成<Kr>。不同的I_K可能导致不同物种的心率不同。

项目成果

A.Shinbo., K.Ono and T.Iijima: "Activation of cardiac ATP-sensitive K^+ channels by KRN4884,a novel K^+ channels opener" Jouranl Physiology and Experimental Therapeutics. 283. 770-777 (1997)

A.Shinbo.、K.Ono 和 T.Iijima：“KRN4884 激活心脏 ATP 敏感 K^ 通道，一种新型 K^ 通道开放剂”《生理学与实验治疗学杂志》。

J.Guo, K.Ono and A.Noma: "Monovalent cation conductance of the sustained current in rabbit sinoatrial node cells" Pflugers Archiv. 433. 209-211 (1996)

J.Guo、K.Ono 和 A.Noma：“兔窦房结细胞中持续电流的单价阳离子电导”Pflugers Archive。

尾野 恭一: "同房結節遅延整流K電流の解析" Therapautic Research. 18. 3537-3542 (1997)

Kyoichi Ono：“同一腔室节点中延迟整流 K 电流的分析”治疗研究 18. 3537-3542 (1997)。

K.Ono, M.Nakao and T.Iijima: "Chloride-and voltage-dependent Ca^<2+> transient in cultured human aortic endothelial cells." Heart and Vessels.Suppl. 12. 50-52 (1997)

K.Ono、M.Nakao 和 T.Iijima：“培养的人主动脉内皮细胞中存在氯化物和电压依赖性 Ca^2 瞬变”。

Y.Tajima, K. Ono and N.Akaike: "Perforate Patch-clamp recording in cardiac myocytes using cation-selective ionophre gramicidin" American Jounal of Physiology. 271. C524-C532 (1996)

Y.Tajima、K. Ono 和 N.Akaike：“使用阳离子选择性离子载体短杆菌肽在心肌细胞中进行穿孔膜片钳记录”《美国生理学杂志》。