Targeted deletion of Kv4.2 eliminates Ito,f and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction
Targeted deletion of Kv4.2 eliminates Ito,f and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction
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DOI：
10.1161/01.res.0000196559.63223.aa
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发表时间：
2005-12-09
影响因子：
20.1
通讯作者：
Nerbonne, JM
中科院分区：
文献类型：
--
作者：
Guo, WN;Jung, WE;Nerbonne, JM
先前的研究已经证明了Kv 4亚家族的电压门控K+（Kv）通道α亚基在产生快速失活/恢复的心脏瞬时外向K+电流I-to、I-f通道中的作用。生化研究表明，小鼠心室Ito，f通道反映了Kv4.2和Kv4.3与辅助亚基KChIP 2和Kv β 1的异聚体组装，并且Kv4.2是（小鼠心室）I-to，I-f密度区域差异的主要决定因素。有趣的是，在不同小鼠模型中操纵I-to、I-f表达的表型结果是不同的。在这里的实验中，检查了Kv4.2（Kv4.2（-/-））的靶向缺失的效果。出乎意料的是，Kv4.2（-/-）心室肌细胞的电压钳记录显示，I-to，I-f被消除。此外，缓慢瞬时外向K+电流I-to、I-s和Kv1.4蛋白（编码I-to、I-s）在Kv4.2（-/-）心室中上调。虽然Kv4.3 mRNA/蛋白表达没有受到可测量的影响，但KChIP 2表达在Kv4.2（-/-）心室中显著降低。与Kv4.3相似，Kv β 1以及Kv1.5和Kv2.1的表达在野生型和Kv4.2（-/-）心室中相似。此外，与之前在表达截短Kv4.2转基因的小鼠中的发现形成鲜明对比，Kv4.2（-/-）小鼠中I-to、I-f的消除不会导致心室肥大。综上所述，这些发现不仅证明了Kv4.2在小鼠心室I-to、I-f通道的产生中的重要作用，而且证明了I-to、I-f通道本身的丧失不具有明显的病理生理学后果。
Previous studies have demonstrated a role for voltage-gated K+ (Kv) channel alpha subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K+ current, I-to,I- f, channels. Biochemical studies suggest that mouse ventricular Ito, f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kv beta 1, and that Kv4.2 is the primary determinant of regional differences in ( mouse ventricular) I-to,I- f densities. Interestingly, the phenotypic consequences of manipulating I-to,I- f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2(-/-)) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2(-/-) ventricular myocytes revealed that I-to,I- f is eliminated. In addition, the slow transient outward K+ current, I-to,I- s, and the Kv1.4 protein (which encodes I-to,I- s) are upregulated in Kv4.2(-/-) ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2(-/-) ventricles. Similar to Kv4.3, expression of Kv beta 1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2(-/-) ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I-to,I- f in Kv4.2(-/-) mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I-to,I- f channels but also that the loss of I-to,I- f per se does not have overt pathophysiological consequences.