Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes

El-Haou, Saïd; Balse, Elise; Neyroud, Nathalie; Dilanian, Gilles; Gavillet, Bruno; Abriel, Hugues; Coulombe, Alain; Jeromin, Andreas; Hatem, Stéphane N.

doi:10.1161/circresaha.108.191007

Cited by 80 publications

(83 citation statements)

References 48 publications

(49 reference statements)

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“…9,10 SAP97 regulates the targeting and localization of cardiac potassium channels, such as Kir2.x 11 and K v 1.5 in myocytes. 10 El-Haou et al 12 recently demonstrated that SAP97 interacts with K v 4.2 and K v 4.3 channels via their PDZ-domain binding motif. They showed that suppression of SAP97 expression in rat myocytes decreases the K v 4.x-mediated current, whereas its overexpression increases it.…”

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confidence: 99%

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Petitprez

Zmoos

Ogrodnik³

et al. 2011

Circulation Research

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Rationale:The cardiac sodium channel Na v 1.5 plays a key role in excitability and conduction. The 3 last residues of Na v 1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na v 1.5 could potentially interact with other, yet unknown, proteins at this site.Objective: The aim of this study was to determine whether Na v 1.5 is part of distinct regulatory complexes at lateral membranes and intercalated discs. Methods and Results:Immunostaining experiments demonstrated that Na v 1.5 localizes at lateral membranes of cardiomyocytes with dystrophin and syntrophin. Optical measurements on isolated dystrophin-deficient mdx hearts revealed significantly reduced conduction velocity, accompanied by strong reduction of Na v 1.5 at lateral membranes of mdx cardiomyocytes. Pull-down experiments revealed that the MAGUK protein SAP97 also interacts with the SIV motif of Na v 1.5, an interaction specific for SAP97 as no pull-down could be detected with other cardiac MAGUK proteins (PSD95 or ZO-1). Furthermore, immunostainings showed that Na v 1.5 and SAP97 are both localized at intercalated discs. Silencing of SAP97 expression in HEK293 and rat cardiomyocytes resulted in reduced sodium current (I Na ) measured by patch-clamp. The I Na generated by Na v 1.5 channels lacking the SIV motif was also reduced. Finally, surface expression of Na v 1.5 was decreased in silenced cells, as well as in cells transfected with SIV-truncated channels. Conclusions:These data support a model with at least 2 coexisting pools of Na v 1.5 channels in cardiomyocytes: one targeted at lateral membranes by the syntrophin-dystrophin complex, and one at intercalated discs by SAP97. (Circ Res. 2011;108:294-304.) Key Words: sodium channel Ⅲ Na v 1.5 Ⅲ MAGUK proteins Ⅲ SAP97 Ⅲ dystrophin T he cardiac sodium channel Na v 1.5 initiates the cardiac action potential, thus playing a key role in cardiac excitability and impulse propagation. The physiological importance of this channel is illustrated by numerous cardiac pathologies caused by hundreds of mutations identified in SCN5A, the gene encoding Na v 1.5. 1 The Na v 1.5 channel is composed of one 220-kDa ␣-subunit that constitutes a functional channel, and 30-kDa ␤-subunits. In addition to these accessory ␤-subunits, several proteins have been shown to regulate and interact with Na v 1.5. 1,2 In most cases, the physiological relevance of these interactions is poorly understood, mainly because of a lack of appropriate animal models. Many of the interacting proteins bind to the C terminus of Na v 1.5, where several protein-protein interaction motifs are located. 1,2 We have shown that the ubiquitin-protein ligase Nedd4-2 binds the PY motif of Na v 1.5 and reduces the sodium current (I Na ) in HEK293 cells by promoting its internalization. 3 We have also demonstrated that Na v 1.5 associates with the dystrophin-syntrophin multiprotein complex (DMC) in cardiac cells. 4 In dystrophin-deficient mice (m...

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SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Petitprez

Zmoos

Ogrodnik³

et al. 2011

Circulation Research

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243

237

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“…Uemura has suggested a molecular role of CaMKII in the ischemic heart, which appeared to be characteristic features reversible and immediate translocation of substantial amounts of CaMKII, and reduced autophosphorylation (Uemura et al, 2002). In addition, the dynamic changes in CaMKII and phospho-CaMKII can also regulate other ion channels of cardiomyocytes, such as potassium and sodium channels (Mori et al, 2000;El-Haou et al, 2009), which have been shown to be involved in Ca 2 + homeostasis in cells.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Alterations in the Ca_V1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts

Zhao

Sun

et al. 2014

DNA and Cell Biology

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Cardiac L-type calcium channel (Ca V 1.2), calmodulin (CaM), and Ca 2 + /calmodulin-dependent protein kinase II (CaMKII) form the Ca V 1.2/CaM/CaMKII signaling pathway, which plays an important role in maintaining intracellular Ca 2 + homeostasis. The roles of CaM and CaMKII in the regulation of Ca V 1.2 in Ca 2 + -dependent inactivation and facilitation have been reported; however, alterations in this signaling pathway in the heart after myocardial ischemia (MI) had not been well characterized. In this study, we investigated the dynamic changes in Ca V 1.2, CaM, and CaMKII mRNA and protein expression levels in the left ventricles of the heart following MI in rats. The MI model was induced by ligating the left anterior descending coronary artery; the rats were divided into the following five groups: the 6 h post-MI group (MI-6h), 24 h post-MI group (MI-24h), 1 week post-MI group (MI-1w), 2 weeks post-MI group (MI-2w), and the sham group. The mRNA levels were measured by quantitative real-time polymerase chain reaction and the protein expression was determined by western blotting and immunohistochemistry. There were no observable differences in the Ca V 1.2 mRNA and protein levels at the early stages of MI, but these levels decreased at MI-2w. Both the mRNA and protein levels of CaM increased at MI-6h, peaked at MI-24h, and then reduced to normal levels at MI-2w. CaMKII mRNA and protein levels decreased at MI-6h and reached their lowest level at MI-24h. Taken together, these data demonstrate that there are dynamic changes in the Ca V 1.2/CaM/CaMKII signaling pathway following MI injuries, which suggests that different therapeutic regimens should be used at different time points after MI injuries.

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Section: Discussionmentioning

confidence: 99%

“…Originally described in the brain at neuronal synapses (75), there is increasing evidence that these scaffolds play a similar role in the heart (1,7,27,39,45,46,53,61,63,81). It has been shown that interaction of cardiac ion channels with SAP97 occurs with a number of potassium channels including Kv1.5, Kv4, Kir2.2 and 2.3, and the hyperpolarization-activated, cyclic nucleotidegated channels (1,7,27,45,46,61,81). These ion channels interact with SAP97 through standard PDZ-domain binding to the terminal most amino acids of the ion channel (1,27,45,46,53,61,81) and appear to play an important role in regulation of channel density at the cardiac myocyte membranes (1,79).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that interaction of cardiac ion channels with SAP97 occurs with a number of potassium channels including Kv1.5, Kv4, Kir2.2 and 2.3, and the hyperpolarization-activated, cyclic nucleotidegated channels (1,7,27,45,46,61,81). These ion channels interact with SAP97 through standard PDZ-domain binding to the terminal most amino acids of the ion channel (1,27,45,46,53,61,81) and appear to play an important role in regulation of channel density at the cardiac myocyte membranes (1,79). We show here direct interaction between Panx1 and SAP97, which is important for Panx1 channel density in the membrane.…”

Section: Discussionmentioning

confidence: 99%

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Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation

Dolmatova

Spagnol

Boassa

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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HS. Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol 303: H1208 -H1218, 2012. First published September 14, 2012; doi:10.1152/ajpheart.00251.2012.-Fibrosis following myocardial infarction is associated with increases in arrhythmias and sudden cardiac death. Initial steps in the development of fibrosis are not clear; however, it is likely that cardiac fibroblasts play an important role. In immune cells, ATP release from pannexin 1 (Panx1) channels acts as a paracrine signal initiating activation of innate immunity. ATP has been shown in noncardiac systems to initiate fibroblast activation. Therefore, we propose that ATP release through Panx1 channels and subsequent fibroblast activation in the heart drives the development of fibrosis in the heart following myocardial infarction. We identified for the first time that Panx1 is localized within sarcolemmal membranes of canine cardiac myocytes where it directly interacts with the postsynaptic density 95/Drosophila disk large/zonula occludens-1-containing scaffolding protein synapseassociated protein 97 via its carboxyl terminal domain (amino acids 300 -357). Induced ischemia rapidly increased glycosylation of Panx1, resulting in increased trafficking to the plasma membrane as well as increased interaction with synapse-associated protein 97. Cellular stress enhanced ATP release from myocyte Panx1 channels, which, in turn, causes fibroblast transformation to the activated myofibroblast phenotype via activation of the MAPK and p53 pathways, both of which are involved in the development of cardiac fibrosis. ATP release through Panx1 channels in cardiac myocytes during ischemia may be an early paracrine event leading to profibrotic responses to ischemic cardiac injury. fibrosis; paracrine signal; sudden cardiac death; ischemia IN CARDIAC INJURY, fibroblasts are activated, causing them to transdifferentiate into myofibroblasts, leading to profibrotic responses such as production of extracellular matrix proteins, collagen, and cytokines (8). With time, expansion of the extracellular matrix leads to separation of surviving myocyte bundles, forming a heterogeneous substrate that leads to slowed conduction which promotes life-threatening arrhythmias. In regions distant to the site of injury, fibroblasts activate and migrate to sites of injury and are highly responsive to cytokines and chemokines (64). While activated fibroblasts are known to produce and secrete many of the signals for myofibroblast formation and migration, thus causing a positive feedback loop of activation, little is known about the initial stimulus within the injured region that begins the activation process. It has been assumed that fibroblasts sense the environment and respond accordingly, but how and what they are sensing during very early stages of cardiac injury are unknown. Our studies suggest that ATP released from cardiac myocyte pannexin 1 (Panx1) channels initiates signaling in fibroblasts to begin the fibrotic process.Panx1 is ubiqui...

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Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes

Cited by 80 publications

References 48 publications

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Dynamic Alterations in the Ca_V1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts

Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation

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Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes

Cited by 80 publications

References 48 publications

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

Dynamic Alterations in the CaV1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts

Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation

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SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Dynamic Alterations in the Ca_V1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts