Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Renal Physiol
2010 Dec 01;2996:F1308-19. doi: 10.1152/ajprenal.00423.2010.
Show Gene links
Show Anatomy links
AMP-activated protein kinase inhibits KCNQ1 channels through regulation of the ubiquitin ligase Nedd4-2 in renal epithelial cells.
Alzamora R
,
Gong F
,
Rondanino C
,
Lee JK
,
Smolak C
,
Pastor-Soler NM
,
Hallows KR
.
???displayArticle.abstract???
The KCNQ1 K(+) channel plays a key role in the regulation of several physiological functions, including cardiac excitability, cardiovascular tone, and body electrolyte homeostasis. The metabolic sensor AMP-activated protein kinase (AMPK) has been shown to regulate a growing number of ion transport proteins. To determine whether AMPK regulates KCNQ1, we studied the effects of AMPK activation on KCNQ1 currents in Xenopus laevis oocytes and collecting duct epithelial cells. AMPK activation decreased KCNQ1 currents and channel surface expression in X. laevis oocytes, but AMPK did not phosphorylate KCNQ1 in vitro, suggesting an indirect regulatory mechanism. As it has been recently shown that the ubiquitin-protein ligase Nedd4-2 inhibits KCNQ1plasma membrane expression and that AMPK regulates epithelial Na(+) channels via Nedd4-2, we examined the role of Nedd4-2 in the AMPK-dependent regulation of KCNQ1. Channel inhibition by AMPK was blocked in oocytes coexpressing either a dominant-negative or constitutively active Nedd4-2 mutant, or a Nedd4-2 interaction-deficient KCNQ1 mutant, suggesting that Nedd4-2 participates in the regulation of KCNQ1 by AMPK. KCNQ1 is expressed at the basolateral membrane in mouse polarized kidney cortical collecting duct (mpkCCD(c14)) cells and in rat kidney. Treatment with the AMPK activators AICAR (2 mM) or metformin (1 mM) reduced basolateral KCNQ1 currents in apically permeabilized polarized mpkCCD(c14) cells. Moreover, AICAR treatment of rat kidney slices ex vivo induced AMPK activation and intracellular redistribution of KCNQ1 from the basolateral membrane in collecting duct principal cells. AICAR treatment also induced increased ubiquitination of KCNQ1 immunoprecipitated from kidney slice homogenates. These results indicate that AMPK inhibits KCNQ1 activity by promoting Nedd4-2-dependent channel ubiquitination and retrieval from the plasma membrane.
Abriel,
Ubiquitylation of ion channels.
2005, Pubmed
Abriel,
Ubiquitylation of ion channels.
2005,
Pubmed
Acharya,
Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium.
2004,
Pubmed
Apodaca,
Receptor-mediated transcytosis of IgA in MDCK cells is via apical recycling endosomes.
1994,
Pubmed
Bacallao,
Preservation of biological specimens for observation in a confocal fluorescence microscope and operational principles of confocal fluorescence microscopy.
1989,
Pubmed
Belfodil,
CFTR-dependent and -independent swelling-activated K+ currents in primary cultures of mouse nephron.
2003,
Pubmed
Bens,
Corticosteroid-dependent sodium transport in a novel immortalized mouse collecting duct principal cell line.
1999,
Pubmed
Bhalla,
Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3.
2005,
Pubmed
Bhalla,
AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2.
2006,
Pubmed
,
Xenbase
Boehmer,
Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B.
2003,
Pubmed
,
Xenbase
Boehmer,
Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination.
2008,
Pubmed
,
Xenbase
Bouley,
Nitric oxide and atrial natriuretic factor stimulate cGMP-dependent membrane insertion of aquaporin 2 in renal epithelial cells.
2000,
Pubmed
Bouley,
Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra).
2005,
Pubmed
Breton,
Cold-induced microtubule disruption and relocalization of membrane proteins in kidney epithelial cells.
1998,
Pubmed
Brown,
Antigen retrieval in cryostat tissue sections and cultured cells by treatment with sodium dodecyl sulfate (SDS).
1996,
Pubmed
Carattino,
Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells.
2005,
Pubmed
,
Xenbase
Carling,
The AMP-activated protein kinase cascade--a unifying system for energy control.
2004,
Pubmed
Corton,
5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?
1995,
Pubmed
Debonneville,
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.
2001,
Pubmed
,
Xenbase
Dieter,
Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB.
2004,
Pubmed
,
Xenbase
Duranton,
KCNQ1 K+ channels are involved in lipopolysaccharide-induced apoptosis of distal kidney cells.
2010,
Pubmed
Eaton,
Regulation of epithelial sodium channel trafficking by ubiquitination.
2010,
Pubmed
Edinger,
Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2.
2009,
Pubmed
,
Xenbase
Embark,
Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms.
2003,
Pubmed
,
Xenbase
Embark,
Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases.
2004,
Pubmed
,
Xenbase
Flores,
The role of Nedd4/Nedd4-like dependant ubiquitylation in epithelial transport processes.
2003,
Pubmed
Gong,
Vacuolar H+-ATPase apical accumulation in kidney intercalated cells is regulated by PKA and AMP-activated protein kinase.
2010,
Pubmed
Gray,
Basolateral K+ conductance in principal cells of rat CCD.
2005,
Pubmed
,
Xenbase
Hallows,
Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation.
2006,
Pubmed
Hallows,
Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells.
2003,
Pubmed
,
Xenbase
Hallows,
Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells.
2003,
Pubmed
,
Xenbase
Hallows,
Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase.
2000,
Pubmed
,
Xenbase
Hallows,
AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells.
2009,
Pubmed
Hallows,
Phosphopeptide screen uncovers novel phosphorylation sites of Nedd4-2 that potentiate its inhibition of the epithelial Na+ channel.
2010,
Pubmed
,
Xenbase
Hallows,
Emerging role of AMP-activated protein kinase in coupling membrane transport to cellular metabolism.
2005,
Pubmed
Hardie,
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.
2007,
Pubmed
Hebert,
Molecular diversity and regulation of renal potassium channels.
2005,
Pubmed
Heitzmann,
No potassium, no acid: K+ channels and gastric acid secretion.
2007,
Pubmed
Henke,
Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1.
2004,
Pubmed
,
Xenbase
Ichimura,
14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase.
2005,
Pubmed
,
Xenbase
Itani,
Nedd4-2 isoforms differentially associate with ENaC and regulate its activity.
2005,
Pubmed
,
Xenbase
Jespersen,
The KCNQ1 potassium channel: from gene to physiological function.
2005,
Pubmed
Jespersen,
The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family.
2007,
Pubmed
Kanki,
A structural requirement for processing the cardiac K+ channel KCNQ1.
2004,
Pubmed
Kunzelmann,
Electrolyte transport in the mammalian colon: mechanisms and implications for disease.
2002,
Pubmed
Lee,
Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2.
2007,
Pubmed
Li,
Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells.
2010,
Pubmed
,
Xenbase
Liu,
Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin.
2010,
Pubmed
Mall,
Role of K(V)LQT1 in cyclic adenosine monophosphate-mediated Cl(-) secretion in human airway epithelia.
2000,
Pubmed
Marx,
Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.
2002,
Pubmed
McCrossan,
The MinK-related peptides.
2004,
Pubmed
,
Xenbase
Melman,
KCNE regulation of KvLQT1 channels: structure-function correlates.
2002,
Pubmed
Moss,
Long QT syndrome: from channels to cardiac arrhythmias.
2005,
Pubmed
Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed
Neumann,
Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli.
2003,
Pubmed
Palmada,
Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1.
2004,
Pubmed
,
Xenbase
Peroz,
Kv7.1 (KCNQ1) properties and channelopathies.
2008,
Pubmed
Seebohm,
Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels.
2007,
Pubmed
,
Xenbase
Snyder,
cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2.
2004,
Pubmed
Vallon,
KCNQ1-dependent transport in renal and gastrointestinal epithelia.
2005,
Pubmed
Vallon,
Role of KCNE1-dependent K+ fluxes in mouse proximal tubule.
2001,
Pubmed
Waldegger,
Heartburn: cardiac potassium channels involved in parietal cell acid secretion.
2003,
Pubmed
Walker,
Activation of AMP-activated protein kinase reduces cAMP-mediated epithelial chloride secretion.
2003,
Pubmed
Warth,
The cAMP-regulated and 293B-inhibited K+ conductance of rat colonic crypt base cells.
1996,
Pubmed
Zheng,
Cellular distribution of the potassium channel KCNQ1 in normal mouse kidney.
2007,
Pubmed
van Balkom,
Hypertonicity is involved in redirecting the aquaporin-2 water channel into the basolateral, instead of the apical, plasma membrane of renal epithelial cells.
2003,
Pubmed
van Bemmelen,
Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination.
2004,
Pubmed
