Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Luo, Lianmin; Ning, Feifei; Du, Yan; Song, Bingxue; Yang, Dandan; Salvage, Samantha C.; Ya, Wang; Fraser, James A.; Zhang, Shetuan; Ma, Aiqun; Wang, Tingzhong

doi:10.1111/apha.12872

Cited by 37 publications

(46 citation statements)

References 45 publications

(59 reference statements)

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“…S2 B ). Calcium overload resulted in ubiquitin‐protein ligase Nedd4‐2‐dependent ubiquitinylation of Nav1.5 and its subsequent degradation through the proteasomal pathway (35). To validate whether Nedd4‐2 mediates I/R‐induced Nav1.5 degradation in our settings, we overexpressed Nedd4‐2 by transfecting Flag‐Nav1.5‐expressing 293T cells with an HA‐Nedd4‐2 plasmid or reduced Nedd4‐2 expression by transfecting these cells with Nedd4‐2 siRNA.…”

Section: Resultsmentioning

confidence: 99%

“…There are basically 2 main cellular processes responsible for protein quality control through removal of damaged or aged proteins: the proteasome system and autophagy (43). Calcium overload results in ubiquitinylation of Nav1.5 and subsequent degradation of Nav1.5 through the Nedd4‐2‐mediated proteasomal pathway in heart failure (35). However, this is not the case in I/R injury‐induced Nav1.5 degradation.…”

Section: Discussionmentioning

confidence: 99%

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AMPK‐mediated degradation of Nav1.5 through autophagy

et al. 2019

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The voltage‐gated cardiac sodium channel, Nav1.5, is the key component that controls cardiac excitative electrical impulse and propagation. However, the dynamic alterations of Nav1.5 during cardiac ischemia and reperfusion (I/R) are seldom reported. We found that the protein levels of rat cardiac Nav1.5 were significantly decreased in response to cardiac I/R injury. By simulating I/R injury in cells through activating AMPK by glucose deprivation, AMPK activator treatment, or hypoxia and reoxygenation (H/R), we found that Nav1.5 was down‐regulated by AMPK‐mediated autophagic degradation. Furthermore, AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule‐associated protein 1 light chain 3 (LC3), by exposing the LC3‐interacting region adjacent to T101 in Nav1.5. This study highlights an instrumental role of AMPK in mediating the autophagic degradation of Nav1.5 during cardiac I/R injury.—Liu, X., Chen, Z., Han, Z., Liu, Y., Wu, X., Peng, Y., Di, W., Lan, R., Sun, B., Xu, B., Xu, W. AMPK‐mediated degradation of Nav1.5 through autophagy. FASEB J. 33, 5366–5376 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AMPK‐mediated degradation of Nav1.5 through autophagy

et al. 2019

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“…A rise in intracellular [Ca 2+ ] has been shown to reduce Na V 1.5 protein expression and the I Na in rat cardiac myocytes . We examined whether a rise in intracellular [Ca 2+ ] would decrease Na X expression.…”

Section: Increased Intracellular [Ca2+] Decreases Nax Protein Levelsmentioning

confidence: 99%

“…A rise in intracellular [Ca 2+ ] has been shown to reduce Na V 1.5 protein expression and the I Na in rat cardiac myocytes. [7][8][9][10] We examined whether a rise in intracellular [Ca 2+ ] would decrease Na X expression. Rat neonatal cardiac myocytes were cultured for 24 hr in growth medium containing 10 mM CaCl 2 and 10 mM KCl to increase cytoplasmic [Ca 2+ ], 7 or 1 mM caffeine to stimulate Ca 2+ release from the sarcoplasmic reticulum.…”

Section: Increased Intracellular [Ca 2 + ] Decreases Na X Protein Lmentioning

confidence: 99%

The sodium channel Na_X: Possible player in excitation–contraction coupling

et al. 2020

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The sodium channel NaX (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage‐gated sodium channels but does not appear to be voltage gated. Although NaX is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of NaX in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of NaX and NaV1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that NaX plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, NaX is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M‐line. Knocking down NaX expression decreased NaV1.5 mRNA and protein and reduced the inward sodium current (INa+) following cell depolarization. When the expression of NaV1.5 was knocked down, ~85% of the INa+ was reduced consistent with the observations that NaV1.5 is the main voltage‐gated sodium channel in cardiac muscle and that NaX likely does not directly participate in mediating the INa+ following depolarization. Silencing NaV1.5 expression led to significant upregulation of NaX mRNA. Similar to NaV1.5, NaX protein levels were rapidly downregulated when the intracellular [Ca2+] was increased either by CaCl2 or caffeine. These data suggest that a relationship exists between NaX and NaV1.5 and that NaX may play a role in excitation–contraction coupling.

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“…Myocardial contractile function is determined by factors such as heart rate, activity of the conduction system, calcium influx causing myocardial fibre shortening and several other modulating factors. Genetic mutations in the SCN5A gene, which encodes the cardiac voltage‐gated sodium channel NaV1.5, may be involved in the pathophysiology of heart failure, in which abnormal NaV1.5 plasma membrane expression and/or sodium current (INa) density have been observed . Excessive sympatho‐excitation characterizes heart failure and contributes to disease progression in CHF.…”

Section: Contractile Function and Heart Failurementioning

confidence: 99%

Current matters of the heart

Persson

2017

Acta Physiologica

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Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Abstract: Calcium-mediated increases in Nedd4-2 downregulate Nav1.5 by ubiquitination. Nav1.5 is downregulated and co-localizes with Nedd4-2 and ubiquitin in failing rat heart. These data suggest a role of Nedd4-2 in Nav1.5 downregulation in HF.

Cited by 37 publications

References 45 publications

AMPK‐mediated degradation of Nav1.5 through autophagy

AMPK‐mediated degradation of Nav1.5 through autophagy

The sodium channel Na_X: Possible player in excitation–contraction coupling

Current matters of the heart

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Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Abstract: Calcium-mediated increases in Nedd4-2 downregulate Nav1.5 by ubiquitination. Nav1.5 is downregulated and co-localizes with Nedd4-2 and ubiquitin in failing rat heart. These data suggest a role of Nedd4-2 in Nav1.5 downregulation in HF.

Cited by 37 publications

References 45 publications

AMPK‐mediated degradation of Nav1.5 through autophagy

AMPK‐mediated degradation of Nav1.5 through autophagy

The sodium channel NaX: Possible player in excitation–contraction coupling

Current matters of the heart

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The sodium channel Na_X: Possible player in excitation–contraction coupling