期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 103, 期 -, 页码 121-136出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.12.006
关键词
Calcineurin; Heart failure; Microdomains; Transmural gradient; Circadian rhythms
资金
- National Institutes of Health [U54 HD087351, HL098051]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico
- FONDECYT
- CONICYT
- Chile [11150282, 79150007]
- PAI Insertion Program
The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure. (C) 2016 Elsevier Ltd. All rights reserved.
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