ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Michlig, Stéphanie; Mercier, A.; Doucet, Alain; Schild, Laurent; Horisberger, Jean‐Daniel; Rossier, Bernard C.; Firsov, Dmitri

doi:10.1074/jbc.m405674200

Cited by 48 publications

(33 citation statements)

References 36 publications

(28 reference statements)

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“…35 Another study found no effect of vasopressin on ERK 1/2 phosphorylation in mouse cortical collecting ducts. 36 In contrast, we found that forskolin stimulates ERK 1/2 phosphorylation, similar to the studies in lung cells, rat CCDs, and mpkCCD c14 cells cited above. 24,28,33 We also found that a MEK 1/2 inhibitor reduced Epac-stimulation of UT-A1 phosphorylation.…”

Section: Basic Research Wwwjasnorgsupporting

confidence: 90%

Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts

Wang

Klein

Blount

et al. 2009

Journal of the American Society of Nephrology

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Urea plays a critical role in the concentration of urine, thereby regulating water balance. Vasopressin, acting through cAMP, stimulates urea transport across rat terminal inner medullary collecting ducts (IMCD) by increasing the phosphorylation and accumulation at the apical plasma membrane of UT-A1. In addition to acting through protein kinase A (PKA), cAMP also activates Epac (exchange protein activated by cAMP). In this study, we tested whether the regulation of urea transport and UT-A1 transporter activity involve Epac in rat IMCD. Functional analysis showed that an Epac activator significantly increased urea permeability in isolated, perfused rat terminal IMCD. Similarly, stimulating Epac by adding forskolin and an inhibitor of PKA significantly increased urea permeability. Incubation of rat IMCD suspensions with the Epac activator significantly increased UT-A1 phosphorylation and its accumulation in the plasma membrane. Furthermore, forskolin-stimulated cAMP significantly increased ERK 1/2 phosphorylation, which was not prevented by inhibiting PKA, indicating that Epac mediated this phosphorylation of ERK 1/2. Inhibition of MEK 1/2 phosphorylation decreased the forskolin-stimulated UT-A1 phosphorylation. Taken together, activation of Epac increases urea transport, accumulation of UT-A1 at the plasma membrane, and UT-A1 phosphorylation, the latter of which is mediated by the MEK-ERK pathway.

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Section: Basic Research Wwwjasnorgsupporting

confidence: 90%

Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts

Wang

Klein

Blount

et al. 2009

Journal of the American Society of Nephrology

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“…Recently, it has been reported that the collecting duct of normal kidney exhibits a significant basal activity of ERK that was not changed by aldosterone or vasopressin. It was concluded that in the principal cell the basal activity of ERK plays a permissive role for Na,K-ATPase function (59). In contrast, there was no clear evidence for a role of ERK activity in ENaC regulation in principal cells under normal conditions, which is consistent with our observation in the oocyte system.…”

Section: Discussionsupporting

confidence: 87%

Stimulation of the Epithelial Sodium Channel (ENaC) by cAMP Involves Putative ERK Phosphorylation Sites in the C Termini of the Channel's β- and γ-Subunit

Yang

Rinke

Korbmacher

2006

Journal of Biological Chemistry

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The mechanisms involved in the regulation of the epithelial sodium channel (ENaC) via the cAMP pathway are not yet completely understood. The aim of the present study was to investigate cAMP-mediated ENaC regulation in Xenopus laevis oocytes heterologously expressing the three subunits (␣␤␥) of rat ENaC and to determine the ENaC regions important for mediating the stimulatory effect of cAMP. In oocytes treated for about 24 h with 1 mM 3-isobutyl-1-methylxanthine (IBMX) and 1 M forskolin (FSK) so as to increase intracellular cAMP, the amiloride-sensitive whole cell current (⌬I Ami ) was on average 10-fold larger than ⌬I Ami in matched control oocytes. This effect on ⌬I Ami was paralleled by an increase in ENaC surface expression caused by a reduced rate of ENaC retrieval. In addition, IBMX/FSK also enhanced ENaC open probability from about 0.2 to 0.5. The stimulatory effect of IBMX/FSK was dependent on the presence of intact PY motifs in the C termini of the channel. Mutagenesis of putative protein kinase A and CK-2 consensus motifs in the cytosolic domains of the channel did not reveal critical sites involved in mediating the stimulatory effect of IBMX/FSK. In contrast, site-directed mutagenesis of two putative ERK-consensus motifs (T613A in ␤ENaC and T623A in ␥ENaC) largely reduced the stimulatory effect of IBMX/FSK. Phosphorylation of these ERK sites has previously been reported to enhance the interaction of ENaC and Nedd4 (Shi, H., Asher, C., Chigaev, A., Yung, Y., Reuveny, E., Seger, R., and Garty, H. (2002) J. Biol. Chem. 277, 13539 -13547). Using co-expression experiments we demonstrated that mutating the two ERK sites attenuates the inhibitory effect of Nedd4-2 on ENaC currents. We conclude that an increase in intracellular cAMP favors the dephosphorylation of the two ERK sites, which reduces channel retrieval and increases P O by modulating ENaC/Nedd4 interaction. This defines a novel regulatory pathway likely to be relevant for cAMP-induced stimulation of ENaC in vivo.The apically localized amiloride-sensitive epithelial sodium channel (ENaC) 2 plays a critical role in fluid and electrolyte homeostasis and is widely expressed in absorptive epithelia such as the aldosterone-sensitive distal nephron, the distal colon, respiratory epithelia, sweat and salivary ducts (1, 2). ENaC is composed of three homologous subunits (␣, ␤, and ␥) that contain two transmembrane domains, a large extracellular loop, and short intracellular amino and carboxyl termini. The functional importance of a highly conserved PPXY sequence (the PY motif) in the carboxyl terminus of each subunit was recognized in Liddle syndrome (3). The PY motifs mediate ENaC binding to WW domains of the ubiquitin ligase Nedd4/Nedd4-2. This binding of Nedd4/Nedd4-2 to ENaC leads to ubiquitination of lysine residues in the N terminus of the channel and to channel internalization and proteasomal degradation (4, 5). In Liddle syndrome, mutations and/or deletions of the PY motif in ␤ or ␥ ENaC reduce the Nedd4/Nedd4-2-mediated endocytic retrieval of ENaC ...

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“…Microdissection was performed in ice-cold DMEM/F-12 (1:1) as described. 20 The following structures were isolated: glomeruli, convoluted and straight proximal tubules, medullary and cortical portions of the thick ascending limb, distal convoluted and connecting tubules, and cortical portions of the collecting ducts. RNA was isolated from microdissected tubules using an RNeasy micro Kit (Qiagen), following the manufacturer's instructions.…”

Section: Surface Biotinylation and Immunoblottingmentioning

confidence: 99%

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

Dhayat

Simonin

Anderegg

et al. 2015

JASN

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A heterozygous mutation (c.643C.A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo. However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G.A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.

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ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Cited by 48 publications

References 36 publications

Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts

Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts

Stimulation of the Epithelial Sodium Channel (ENaC) by cAMP Involves Putative ERK Phosphorylation Sites in the C Termini of the Channel's β- and γ-Subunit

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

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