Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b

Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael; Prehar, Sukhpal; Baudoin, Florence; Zi, Min; Alatwi, Nasser; Venetucci, Luigi; Schuh, Kai; Williams, Judith C.; Armesilla, Ángel Luis; Neyses, Ludwig

doi:10.1161/circulationaha.106.643791

Cited by 100 publications

(101 citation statements)

References 44 publications

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“…Interestingly, although CAPON overexpression activates NOS1-derived NO in our work, the electrophysiological changes mediated by this NO activation are comparable with those in previous reports (17)(18)(19)21). Recently, evidence emerged that NOS1 may play a critical role in the regulation of calcium handling and myocyte contraction in the heart (9,10,12,22). Burkard et al (12) observed that in a conditional NOS1-overexpressing transgenic mouse model, the peak I Ca,L density was significantly reduced by 39% in NOS1-overexpressing ventricular myocytes, which was attributed to the translocation of NOS1 to sarcolemma where NOS1 interacted with L-type calcium channel and caused inhibition of I Ca,L .…”

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalsupporting

confidence: 91%

“…This investigation might be of particular importance, because NOS1-NO pathways have recently been related to play a role in regulating cardiac contractility (9,10,12). Moreover, because CAPON may compete with other PDZ-binding proteins for PDZ binding, it is likely that CAPON, in addition to modulating the NOS1-NO pathway, might also have other biological effects, particularly regarding stabilization of cell membrane proteins, including ion channels.…”

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalmentioning

confidence: 99%

“…NOS1 in the sarcolemma has been proposed to interact with Na ϩ -K ϩ ATPase (8) and with the plasma membrane Ca 2ϩ /calmodulin-dependent Ca 2ϩ ATPase (PMCA) through the interaction of PDZ domain of NOS1 and the C terminus of PMCA4b isoform (9). In the sarcoplasmic reticulum (SR), NOS1 is structurally associated with ryanodine receptor 2 (RyR2) (10) and cardiac SR Ca 2ϩ ATPase (SERCA2) (11) to regulate intracellular calcium cycling and excitation-contraction coupling.…”

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confidence: 99%

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CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

Chang

Barth

Sasano

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

117

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Congenital long-or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from the rare disease-causing mutations, common genetic variants in CAPON, a neuronal nitric oxide synthase (NOS1) regulator, have recently been associated with QT interval variations in a human whole-genome association study. CAPON had been unsuspected of playing a role in cardiac repolarization; indeed, its physiological role in the heart (if any) is unknown. To define the biological effects of CAPON in the heart, we investigated endogenous CAPON protein expression and protein-protein interactions in the heart and performed electrophysiological studies in isolated ventricular myocytes with and without CAPON overexpression. We find that CAPON protein is expressed in the heart and interacts with NOS1 to accelerate cardiac repolarization by inhibition of L-type calcium channel. Our findings provide a rationale for the association of CAPON gene variants with extremes of the QT interval in human populations.NOS1 ͉ QT interval ͉ cardiac electrophysiology R are disease-causing mutations leading to congenital long-or short-QT syndrome are well recognized, but there is little insight into genetic sources of QT interval variation in normal populations. A whole-genome association approach has recently implicated common genetic variants in CAPON as contributing to QT interval differences in a community-based German population (1). This association has since been confirmed in other populations (2, 3). The genetic findings challenge our current understanding of QT physiology. CAPON, first identified in rat brain neurons (4), is a highly conserved protein (Ϸ92% conceptual amino acid sequence identity between rat and human) with an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal PDZ-binding [postsynaptic density-95 (PSD95)/drosophila discs large/zona occludens-1] domain (4-6). In brain, CAPON competes with PSD95 for the binding of neuronal nitric oxide synthase (NOS1) through the interaction of its C terminus with the PDZ domain of NOS1 (4), thus uncoupling the NMDA-NOS1-NO-mediated signaling pathways. CAPON is also an adaptor protein of NOS1, capable of directing NOS1 to specific target proteins (5, 6). Nowhere, however, has CAPON been suspected of playing a role in cardiac physiology.Both NOS1 and endothelial NOS (NOS3) are constitutively expressed in cardiomyocytes (7). NOS1 in the sarcolemma has been proposed to interact with Na ϩ -K ϩ ATPase (8) and with the plasma membrane Ca 2ϩ /calmodulin-dependent Ca 2ϩ ATPase (PMCA) through the interaction of PDZ domain of NOS1 and the C terminus of PMCA4b isoform (9). In the sarcoplasmic reticulum (SR), NOS1 is structurally associated with ryanodine receptor 2 (RyR2) (10) and cardiac SR Ca 2ϩ ATPase (SERCA2) (11) to regulate intracellular calcium cycling and excitation-contraction coupling. Conditional transgenic overexpression of NOS1 in heart leads to additional association of NOS1 and the sarcolemmal L-type calcium channel and thus suppresses...

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Section: Reversal Of Capon Overexpression-induced Electrophysiologicalsupporting

confidence: 91%

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalmentioning

confidence: 99%

mentioning

confidence: 99%

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CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

Chang

Barth

Sasano

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

117

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“…In isolated molecular experiments, cardiomyocytes and whole heart tissue PMCA4 functionally associate with calcineurin (Buch et al, 2005), Ras-associated factor 1 (Armesilla et al, 2004), α1-syntrophin (Williams et al, 2006) and nNOS, the latter via interaction with the PDZ domain on PMCA4 (Schuh et al, 2001;Oceandy et al, 2007;Duan et al, 2013). In blood vessels any such association of PMCA4 and nNOS clearly appears to be of relevance to the regulation of arterial contractility.…”

Section: Transgenic Expression Of Plasma Membrane Calcium Atpasementioning

confidence: 99%

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

Little

Cartwright

Neyses

et al. 2016

Pharmacology & Therapeutics

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The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1, encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP.

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“…Two main characteristics of a signaling molecule displayed by PMCA are the ability to interact with signaling proteins (3) and its localization in caveolae (4). Recent evidence from our laboratory suggested that PMCA has a role in mediating nNOS activity (5,6) and demonstrated the physiological relevance of this novel signaling complex in regulating cardiac contractility (7,8).…”

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confidence: 99%

Measurement of Plasma Membrane Calcium–Calmodulin-Dependent ATPase (PMCA) Activity

Mohamed

Baudoin

Abouleisa

et al. 2010

Methods in Molecular Biology

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The plasma membrane calcium-calmodulin-dependent ATPase (PMCA) is a calcium-extruding enzymatic pump that ejects calcium from the cytoplasm to the extracellular compartment. Although in excitable cells such as skeletal and cardiac muscle cells PMCA has been shown to play only a minor role in regulating global intracellular calcium concentration, increasing evidence points to an important role for PMCA in signal transduction, in particular in the nitric oxide signaling pathway. Moreover, recent evidence has shown the functional importance of PMCA in mediating cardiac contractility and vascular tone. Here we describe a method in determining PMCA activity in the microsomal membrane preparation from cultured cells that overexpress specific isoform of PMCA by using modified coupled enzyme assay.

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Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b

Cited by 100 publications

References 44 publications

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

Measurement of Plasma Membrane Calcium–Calmodulin-Dependent ATPase (PMCA) Activity

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