Regulation of the Human Ether-a-go-go-related Gene (hERG) Channel by Rab4 Protein through Neural Precursor Cell-expressed Developmentally Down-regulated Protein 4-2 (Nedd4-2)

Cui, Zhi; Zhang, Shetuan

doi:10.1074/jbc.m113.461715

Cited by 27 publications

(25 citation statements)

References 56 publications

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“…To further test the involvement of Nedd4-2 in the carbachol-induced enhancement of hERG channels, we investigated the effect of carbachol on two hERG mutants, point mutation Y1078A and C-terminal truncation mutation D1073 stably expressed in HEK cells. These two mutants have a disrupted Nedd4-2 binding site (Guo et al, 2012;Cui and Zhang, 2013;Lamothe and Zhang, 2013). As shown in Fig.…”

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 97%

“…Recently, we demonstrated that hERG channels are regulated by an E3 ubiquitin ligase, Nedd4-2 (Guo et al, 2012;Cui and Zhang, 2013;Lamothe and Zhang, 2013). Nedd4-2 contains a C2 domain, four WW domains, and a catalytic HECT domain (Ingham et al, 2004).…”

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 99%

“…The WW domain of the Nedd4-2 protein recognizes substrates for ubiquitination by binding to the PPxY motif. Nedd4-2 then transfers Ub from the HECT domain to the lysine residues of hERG proteins, leading to the internalization of hERG channels from the cell membrane (Guo et al, 2012;Cui and Zhang, 2013;Lamothe and Zhang, 2013). To investigate the role of Nedd4-2 in the carbachol-induced augmentation of hERG channels, we studied the hERGNedd4-2 interaction using co-IP analysis.…”

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 99%

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Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Wang¹,

Hogan-Cann²,

Kang³

et al. 2014

Mol Pharmacol

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The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel, which is important for cardiac repolarization. Reduction of hERG current due to genetic mutations or drug interferences causes long QT syndrome, leading to cardiac arrhythmias and sudden death. To date, there is no effective therapeutic method to restore or enhance hERG channel function. Using cell biology and electrophysiological methods, we found that the muscarinic receptor agonist carbachol increased the expression and function of hERG, but not ether-à-go-go or K v 1.5 channels stably expressed in human embryonic kidney cells. The carbachol-mediated increase in hERG expression was abolished by the selective M3 antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide) but not by the M2 antagonistTreatment of cells with carbachol reduced the hERG-ubiquitin interaction and slowed the rate of hERG degradation. We previously showed that the E3 ubiquitin ligase Nedd4-2 mediates degradation of hERG channels. Here, we found that disrupting the Nedd4-2 binding domain in hERG completely eliminated the effect of carbachol on hERG channels. Carbachol treatment enhanced the phosphorylation level, but not the total level, of Nedd4-2. Blockade of the protein kinase C (PKC) pathway abolished the carbachol-induced enhancement of hERG channels. Our data suggest that muscarinic activation increases hERG channel expression by phosphorylating Nedd4-2 via the PKC pathway.

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Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 97%

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 99%

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 99%

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Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Wang¹,

Hogan-Cann²,

Kang³

et al. 2014

Mol Pharmacol

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“…Rab4 and Rab11 regulate the transport along the recycling pathway, from early and recycling endosomes to the cell surface (van der Ullrich et al 1996). Rab4 regulates the recycling of integrins, receptors, ubiquitin ligases, and other transport machinery (Arjonen et al 2012;Cheng et al 2013;Cui and Zhang 2013). Rab11 isoforms and their downstream effectors have critical roles in cell polarity, and defects underlie cancer, gastrointestinal, and degenerative disease (for reviews, see Jing and Prekeris 2009;Kelly et al 2012;Mitra et al 2012).…”

Section: Rab Gtpases On the Endocytic Pathway Compartmentalize Endocymentioning

confidence: 99%

Rab Proteins and the Compartmentalization of the Endosomal System

Wandinger‐Ness

Zerial

2014

Cold Spring Harbor Perspectives in Biology

509

469

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Of the approximately 70 human Rab GTPases, nearly three-quarters are involved in endocytic trafficking. Significant plasticity in endosomal membrane transport pathways is closely coupled to receptor signaling and Rab GTPase-regulated scaffolds. Here we review current literature pertaining to endocytic Rab GTPase localizations, functions, and coordination with regulatory proteins and effectors. The roles of Rab GTPases in (1) compartmentalization of the endocytic pathway into early, recycling, late, and lysosomal routes; (2) coordination of individual transport steps from vesicle budding to fusion; (3) effector interactomes; and (4) integration of GTPase and signaling cascades are discussed.

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“…23 Even considering an ENaC-directed therapeutic regimen, Rab4 is known to participate in the regulation of density at the plasma membrane of hERG (ether-a-go-go-related), the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). 54 A reduction in the hERG current causes long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. Consequently, any interference with Rab4 should always be monitored for its short and long-term effects in the heart.…”

Section: Rab Proteins As Putative Therapeutic Targetsmentioning

confidence: 99%

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

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Regulation of the Human Ether-a-go-go-related Gene (hERG) Channel by Rab4 Protein through Neural Precursor Cell-expressed Developmentally Down-regulated Protein 4-2 (Nedd4-2)

Cited by 27 publications

References 56 publications

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Rab Proteins and the Compartmentalization of the Endosomal System

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

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