Article

Calcium Cycling and Signaling in Cardiac Myocytes

Department of Physiology and Cardiovascular Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Annual Review of Physiology (Impact Factor: 18.51). 02/2008; 70(1):23-49. DOI: 10.1146/annurev.physiol.70.113006.100455
Source: PubMed

ABSTRACT

Calcium (Ca) is a universal intracellular second messenger. In muscle, Ca is best known for its role in contractile activation. However, in recent years the critical role of Ca in other myocyte processes has become increasingly clear. This review focuses on Ca signaling in cardiac myocytes as pertaining to electrophysiology (including action potentials and arrhythmias), excitation-contraction coupling, modulation of contractile function, energy supply-demand balance (including mitochondrial function), cell death, and transcription regulation. Importantly, although such diverse Ca-dependent regulations occur simultaneously in a cell, the cell can distinguish distinct signals by local Ca or protein complexes and differential Ca signal integration.

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    • "Cyclic adenosine 3 ′ ,5 ′ -monophosphate (cAMP) is the main second messenger of the β-adrenergic receptor signaling inducing phosphorylation of the LTCC and the ryanodine receptor to increase the amount of intracellular Ca 2+ necessary for heart contractility (responsible for positive chronotropic and inotropic effects during sympathetic stimulation) (Guellich et al., 2014). Moreover, catecholamine stimulated β-adrenergic receptor not only leads to cAMP effector dependent-troponin I phosphorylation to allow faster force development and shortening during systole and faster force relaxation and re-lengthening during diastole but also mediated cAMP effector dependent-phospholamban phosphorylation responsible for Ca 2+ re-uptake in the sarcoplasmic reticulum and myofilament relaxation (lusitropic effects) (Bers, 2008). However sustained stimulation of this pathway may be detrimental thus leading to cardiac remodeling and development of heart failure (Brodde, 1993; Kiuchi et al., 1993). "
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    ABSTRACT: Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.
    Full-text · Article · Oct 2015 · Frontiers in Pharmacology
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    • "β 1 and β 2 receptors activate G s proteins (stimulatory G proteins), which initiate the adenosine 3',5'-monophosphate or cyclic AMP (cAMP) pathway in the heart, thereby activating cAMP-dependent protein kinase (protein kinase A, PKA) (Lymperopoulos et al., 2013; Bers, 2008) (Fig. 1). PKA is the major effector of cAMP and, by phosphorylating several substrates, ultimately results in increased intracellular Ca 2 þ concentration, which is the master regulator of cardiac muscle contraction (Fig. 1) (Bers, 2008). Of note, PKA can phosphorylate the β receptors themselves (and other GPCRs) in the heart, causing G protein uncoupling and functional desensitization of the receptor (heterologous or agonist-independent desensitization). "
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    ABSTRACT: G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · May 2015 · European journal of pharmacology
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    • "This approximately 10-fold increase in cytosolic calcium concentration activates calcium-sensitive contractile proteins (troponin C; TN-C), which then use ATP to produce tension and muscle contraction. For muscle relaxation to occur, calcium is removed from the cytosol—approximately 30% is transported out of the cell (primarily by the sodium-calcium exchanger [NCX] and plasma membrane calcium ATPase [PMCA]) while 70% is pumped back into the SR via the cardiac SR calcium ATPase (SERCA2a) (Bers, 2008). "
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    ABSTRACT: Cardiomyocyte function depends on coordinated movements of calcium into and out of the cell and the proper delivery of ATP to energy-utilizing enzymes. Defects in calcium-handling proteins and abnormal energy metabolism are features of heart failure. Recent discoveries have led to gene-based therapies targeting calcium-transporting or -binding proteins, such as the cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a), leading to improvements in calcium homeostasis and excitation-contraction coupling. Here we review impaired calcium cycling and energetics in heart failure, assessing their roles from both a mutually exclusive and interdependent viewpoint, and discuss therapies that may improve the failing myocardium. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell Metabolism
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