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首页> 外文期刊>Biochemical Pharmacology >Regulation of Kv4.3 and hERG potassium channels by KChIP2 isoforms and DPP6 and response to the dual K+ channel activator NS3623
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Regulation of Kv4.3 and hERG potassium channels by KChIP2 isoforms and DPP6 and response to the dual K+ channel activator NS3623

机译：通过Kchip2同种型和DPP6调节KV4.3和HERG钾通道，并响应双K +通道激活剂NS3623

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摘要

Transient outward potassium current (I-to) contributes to early repolarization of many mammalian cardiac action potentials, including human, whilst the rapid delayed rectifier K+ current (I-kr) contributes to later repolarization. Fast I-to channels can be produced from the Shat family KCNDE gene product Kv4.3s, although accessory subunits including KChIP2.x and DPP6 are also needed to produce a near physiological I-to. In this study, the effect of KChIP2.1 & KChIP2.2 (also known as KChIP2b and KChIP2c respectively), alone or in conjunction with the accessory subunit DPP6, on both Kv4.3 and hERG were evaluated. A dual I-to and I-Kr activator, NS3623, has been recently proposed to be beneficial in heart failure and the action of NS3623 on the two channels was also investigated. Whole-cell patch-clamp experiments were performed at 33 +/- 1 degrees C on HEK293 cells expressing Kv4.3 or hERG in the absence or presence of these accessory subunits. Kv4.3 current magnitude was augmented by co-expression with either KChIP2.2 or KChIP2.1 and KChIP2/DPP6 with KChIP2.1 producing a greater effect than KChIP2.2. Adding DPP6 removed the difference in Kv4.3 augmentation between KChIP2.1 and KChIP2.2. The inactivation rate and recovery from inactivation were also altered by KChIP2 isoform co-expression. In contrast, hERG (Kv11.1) current was not altered by co-expression with KChIP2.1, KChIP2.2 or DPP6. NS3623 increased Kv4.3 amplitude to a similar extent with and without accessory subunit co-expression, however KChIP2 isoforms modulated the compound's effect on inactivation time course. The agonist effect of NS3623 on hERG channels was not affected by KChIP2.1, KChIP2.2 or DPP6 co-expression.
机译：瞬态向外钾电流（I-to）有助于许多哺乳动物心脏作用潜力的早期倒钩，包括人，而快速延迟整流k +电流（I-KR）有助于后来的再渗。尽管包括Kchip2.x和DPP6的附件亚基，但也可以从Shat Family KCNDE基因产品KV4.3s生产快速i-to频道。在该研究中，评估Kchip2.1和Kchip2.2（分别称为Kchip2b和Kchip2c的kchip2c）的效果，单独或与kv4.3和herg的辅助亚单位dpp6一起进行。最近已经提出了双I-to和I-KR激活剂，NS3623，在心力衰竭中有益，并且还研究了两种通道上的NS3623的作用。在没有或存在这些附件亚基的HEK293细胞上，在33 +/- 1℃下进行全细胞贴片实验。 KV4.3通过与Kchip2.2或Kchip2.1和Kchip2 / DPP6的共同表达来增强kV4.3的电流幅度和kchip2.1产生比kchip2.2更大的效果。添加DPP6删除了Kchip2.1和Kchip2.2之间的KV4.3增强的差异。通过Kchip2同种型共表达也改变了失活率和灭活的恢复。相反，HERG（KV11.1）电流没有通过与KCHIP2.1，KCHIP2.2或DPP6共表达而改变。 NS3623增加了kV4.3的幅度与具有辅助亚基共同表达的类似程度，但是Kchip2同种型调节了化合物对灭活时间过程的影响。 NS3623对HERG通道的激动剂效应不受KCHIP2.1，KCHIP2.2或DPP6共表达的影响。

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