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The L-type calcium channel in the heart: the beat goes on
Ilona Bodi, … , Shahab A. Akhter, Arnold Schwartz
Ilona Bodi, … , Shahab A. Akhter, Arnold Schwartz
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3306-3317. https://doi.org/10.1172/JCI27167.
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Review Article has an altmetric score of 18

The L-type calcium channel in the heart: the beat goes on

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Abstract

Sydney Ringer would be overwhelmed today by the implications of his simple experiment performed over 120 years ago showing that the heart would not beat in the absence of Ca2+. Fascination with the role of Ca2+ has proliferated into all aspects of our understanding of normal cardiac function and the progression of heart disease, including induction of cardiac hypertrophy, heart failure, and sudden death. This review examines the role of Ca2+ and the L-type voltage-dependent Ca2+ channels in cardiac disease.

Authors

Ilona Bodi, Gabor Mikala, Sheryl E. Koch, Shahab A. Akhter, Arnold Schwartz

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Figure 1

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A model illustrating the Ca2+ signaling pathways implicated in hypertrop...
A model illustrating the Ca2+ signaling pathways implicated in hypertrophy and heart failure. Stimulation of the β1-AR activates Gs (stimulatory G protein),, which activates adenylyl cyclase (AC), causing production of cAMP. This stimulates cAMP-dependent PKA, which phosphorylates (P) and alters the function of numerous substrates important for SR Ca2+ regulation, including the L-VDCC, RyR2, and phospholamban (PLN). β2-ARs couple Gi/Ras/MEK1/2/ERK1/2 pathways to hypertrophy (Gi, inhibitory G protein; MEK1/2, mitogen-activated protein kinase kinase). Subsequently, the activated β1-AR is desensitized when it is phosphorylated by β-AR kinase-1 (βARK1). During hypertrophy, β1-AR expression increases. In heart failure, while the levels of PLN protein expression remain unchanged (or decreased), the phosphorylation status at Ser16 and Thr17 is decreased, even though the levels of SR Ca2+-ATPase 2a (SERCA2a) are decreased. Cardiac SR-associated protein phosphatase-1 (PP-1) removes phosphate at Ser16 in PLN and is upregulated in heart failure. Calstabin2 (FKB12.6) plays a role in stabilizing RyR2 in order to help maintain the channel in a closed state during diastole. RyR2 is hyperphosphorylated in heart failure, and calstabin2 dissociates from RyR2. Elevated NCX is an adaptive change in heart failure that becomes maladaptive and may be responsible for both arrhythmogenesis and contractile dysfunction. PKC-α expression and activity are elevated in heart failure. Calcineurin (CN) is activated by sustained elevation of [Ca2+]i. It dephosphorylates nuclear factor of activated T cells (NFAT), enabling its translocation to the nucleus, which is sufficient to induce hypertrophy. Hypertrophic stimuli, such as α1-adrenergic agonists, Ang II, and endothelin-1 (ET-1), all elevate [Ca2+]i and activate the CN-NFAT, Ca2+/CaM-CaMKII, and PKC-MAPK-NFAT signaling systems through G protein–coupled receptors (GPCRs) and PLC-DAG-IP3–dependent Ca2+ release [PLC, phospholipase C; DAG, diacylglycerol, IP3, inositol (1,4,5)-trisphosphate]. Transcription factors, such as myocyte-enhancer factor 2 (MEF2) and GATA4 (cardiac zinc finger transcription factor) are located in the nucleus and serve as endpoints for hypertrophic-signaling pathways. AT1, type 1 angiotensin II receptors; Giβγ, βγ subunit of the activated Gi-binding protein; Gq, heterotrimeric GTP-binding protein, consisting of Gα and Gβγ, which dissociate upon receptor activation; NHE, Na+/H+ exchanger, regulates cytosolic pH; PIP2, phosphatidylinositol 4,5-biphosphate; T tubule, transverse tubule.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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