Beta-adrenergic receptor signaling in the heart: role of CaMKII.
Beta-adrenergic receptor signaling in the heart: role of CaMKII.
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DOI：
10.1016/j.yjmcc.2009.10.016
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发表时间：
2010-02
影响因子：
5
通讯作者：
Brown JH
中科院分区：
文献类型：
--
作者：
Grimm M;Brown JH
多功能Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）靶向许多Ca 2+稳态蛋白并调节基因转录。许多被CaMKII磷酸化的底物也是蛋白激酶A（PKA）的底物，PKA是β-肾上腺素能受体（β-AR）信号传导的最知名的下游效应物。虽然PKA和CaMKII通常被认为是通过不同的途径来调节信号，但有大量证据表明CaMKII响应于β-AR刺激而被激活，并且β-AR刺激的一些下游效应实际上是由CaMKII介导的。β-AR刺激激活CaMKII的信号通路（与PKA平行或在PKA下游）尚未明确。本文综述了CaMKII在β-AR刺激下被激活的证据和机制。此外，还考虑了CaMK Ⅱ在β-AR调节心脏功能中的潜在作用。值得注意的是，尽管许多CaMKII靶点（例如，受磷蛋白（phospholamban）或兰尼碱受体（ryanodine receptor）对Ca 2+处理的调节是中心的，并且CaMKII对Ca 2+处理的作用是可检测的，CaMKII的抑制或基因缺失对β-AR的急性生理收缩反应具有相对较小的影响。另一方面，CaMK II表达和活性在心力衰竭中增加，心力衰竭是一种以心脏β-AR的慢性刺激为特征的病理生理学状况。阻断β-AR是治疗慢性心力衰竭的公认疗法，尽管其在心肌细胞中的有益作用的原理尚不确定。越来越多的证据表明，CaMKII的抑制或基因缺失也对心力衰竭的发展具有显著的有益影响。过度的β-AR刺激可能是有害的，因为它对CaMKII介导的Ca 2+处理障碍（例如，Ryanodine受体磷酸化和舒张期SR Ca 2+泄漏）是一个有趣的假设，值得将来考虑。
The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) targets a number of Ca2+ homeostatic proteins and regulates gene transcription. Many of the substrates phosphorylated by CaMKII are also substrates for protein kinase A (PKA), the best known downstream effector of β-adrenergic receptor (β-AR) signaling. While PKA and CaMKII are conventionally considered to transduce signals through separate pathways, there is a body of evidence suggesting that CaMKII is activated in response to β-AR stimulation and that some of the downstream effects of β-AR stimulation are actually mediated by CaMKII. The signaling pathway through which β-AR stimulation activates CaMKII, in parallel with or downstream of PKA, is not well-defined. This review considers the evidence for and mechanisms by which CaMKII is activated in response to β-AR stimulation. In addition the potential role of CaMKII in β-AR regulation of cardiac function is considered. Notably, although many CaMKII targets (e.g., phospholamban or the ryanodine receptor) are central to the regulation of Ca2+ handling, and effects of CaMKII on Ca2+ handling are detectable, inhibition or gene deletion of CaMKII has relatively little effect on the acute physiological contractile response to β-AR. On the other hand CaMKII expression and activity are increased in heart failure, a pathophysiological condition characterized by chronic stimulation of cardiac β-ARs. Blockade of β-ARs is an accepted therapy for treatment of chronic heart failure although the rationale for its beneficial effects in cardiomyocytes is uncertain. There is growing evidence that inhibition or gene deletion of CaMKII also has a significant beneficial impact on the development of heart failure. The possibility that excessive β-AR stimulation is detrimental because of its effects on CaMKII mediated Ca2+ handling disturbances (e.g., ryanodine receptor phosphorylation and diastolic SR Ca2+ leak) is an intriguing hypothesis that merits future consideration.
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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DOI：
10.1073/pnas.0812536106
发表时间：
2009-08-18
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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