title: Calcineurin signaling in the heart: The importance of time and place.
abstract: 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.
authors.affiliation: Advanced Centre for Chronic Disease (ACCDiS), Facultad Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago,Chile; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chie, Santiago, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.affiliation: Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Centre, Dallas, TX, USA; Department of Molecular Biology, University of Texas Southwestern Medical Centre, Dallas, TX, USA. Electronic address: beverly.rothermel@utsouthwestern.edu.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D014157:Transcription Factors; D019703:Calcineurin
keywords: Calcineurin; Circadian rhythms; Heart failure; Microdomains; Transmural gradient