Calcineurin increases cardiac transient outward K+ currents via transcriptional up-regulation of Kv4.2 channel subunits
Calcineurin increases cardiac transient outward K+ currents via transcriptional up-regulation of Kv4.2 channel subunits
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DOI：
10.1074/jbc.m607774200
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发表时间：
2006-12-15
影响因子：
4.8
通讯作者：
Backx, Peter H.
中科院分区：
文献类型：
--
作者：
Gong, Nanling;Bodi, Ilona;Backx, Peter H.
快速瞬态外向钾电流（I-to、I-f）是心肌细胞复极化和心肌细胞收缩性区域异质性的关键决定因素。此外，在心脏肥大和心脏病中，I-to,I-f 密度显着下调，这些疾病与丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶 (Cn) 的激活有关。在这项研究中，我们研究了在有或没有用去氧肾上腺素（PE）刺激α（1）-肾上腺素受体的情况下培养的新生大鼠心室肌细胞（NRVM）中Cn对I-to,I-f表达的调节。 NRVM 中组成型活性 Cn 的过度表达可诱导肥大，并导致 I-to,I-f 密度以及 Kv4.2 mRNA 和蛋白表达以及启动子活性显着增加，而不影响 Kv4.3 或 KChIP2 水平。 Cn 对肥大、I-to、I-f 和 Kv4.2 转录的影响与 NFAT 激活相关，并可通过 NFAT 抑制而消除。尽管激活 Cn 并诱导 NRVM 肥大，PE 仍导致 I-to,I-f 密度以及 Kv4.2、Kv4.3 和 KChIP2 表达的深度下调。尽管肥大和 NFAT 激活被 Cn 抑制肽 CAIN 抑制，但 CAIN 进一步降低了 I-to、I-f 和 Kv4.2 表达，而 Cn 过表达消除了 PE 诱导的 I-to、I-f 和 Kv4.2 表达减少，而不影响 Kv4.3 或 KChIP2 水平。我们得出结论，Cn 通过正向调节 Kv4.2 基因转录来增加心脏 I-to,I-f 密度。与这一结论一致，我们发现在心脏病发生之前从过度表达 Cn 的幼鼠中分离出的肌细胞中 I-to,I-f 增加。这种通过 Cn 激活对 Kv4.2 转录的正向调节有望最大限度地减少肥大心肌细胞中观察到的 Ito、f 和 Kv4.2 表达的减少。
Fast transient outward potassium currents (I-to,I- f) are critical determinants of regional heterogeneity of cardiomyocyte repolarization as well as cardiomyocyte contractility. Additionally, I-to,I- f densities are markedly down-regulated in cardiac hypertrophy and heart disease, conditions associated with activation of the serine/threonine phosphatase calcineurin (Cn). In this study, we investigated the regulation of I-to,I- f expression by Cn in cultured neonatal rat ventricular myocytes (NRVMs) with and without alpha(1)-adrenoreceptor stimulation with phenylephrine ( PE). Overexpression of constitutively active Cn in NRVMs induced hypertrophy and caused profound increases in I-to,I- f density as well as Kv4.2 mRNA and protein expression and promoter activity, without affecting Kv4.3 or KChIP2 levels. The effects of Cn on hypertrophy, I-to,I- f, and Kv4.2 transcription were associated with NFAT activation and were abrogated by NFAT inhibition. Despite activating Cn and inducing hypertrophy in NRVMs, PE resulted in profound down-regulation of I-to,I- f densities as well as Kv4.2, Kv4.3, and KChIP2 expression. Although hypertrophy and NFAT activation were inhibited by the Cn inhibitory peptide CAIN, I-to,I- f and Kv4.2 expression were further reduced by CAIN, whereas Cn overexpression eliminated PE-induced reductions in I-to,I- f and Kv4.2 expression without affecting Kv4.3 or KChIP2 levels. We conclude that Cn increases cardiac I-to,I- f densities by positively regulating Kv4.2 gene transcription. Consistent with this conclusion, we found that I-to,I- f was increased in myocytes isolated from young mice overexpressing Cn prior to the development of heart disease. This positive regulation of Kv4.2 transcription by Cn activation is expected to minimize the reductions in Ito, f and Kv4.2 expression observed in hypertrophic cardiomyocytes.