Secretory Carrier Membrane Protein 2 Regulates Cell-surface Targeting of Brain-enriched Na+/H+ Exchanger NHE5

Diering, Graham H.; Church, John A.; Numata, Masayuki

doi:10.1074/jbc.m807055200

Cited by 30 publications

(18 citation statements)

References 78 publications

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“…Additional evidence for the specificity of SCAMP2 action on NKCC2 stems from the observation that SCAMP2 did not influence the distribution of Rab11 and internalized transferrin. Moreover, the specificity of SCAMP2-induced down-regulation of NKCC2 surface expression is also supported by a previous report demonstrating that NHE-5 interaction with overexpressed SCAMP2 in recycling endosomes promotes the cell surface targeting of the exchanger protein (59). Taken together, these findings suggest strongly that SCAMP2 specifically regulates NKCC2 transit through recycling endosomes to inhibit its cell surface targeting.…”

Section: Discussionsupporting

confidence: 75%

Secretory Carrier Membrane Protein 2 Regulates Exocytic Insertion of NKCC2 into the Cell Membrane

Zaarour

Defontaine

Demaretz

et al. 2011

Journal of Biological Chemistry

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The renal-specific Na-K-2Cl co-transporter, NKCC2, plays a pivotal role in regulating body salt levels and blood pressure. NKCC2 mutations lead to type I Bartter syndrome, a life-threatening kidney disease. Regulation of NKCC2 trafficking behavior serves as a major mechanism in controlling NKCC2 activity across the plasma membrane. However, the identities of the protein partners involved in cell surface targeting of NKCC2 are largely unknown. To gain insight into these processes, we used a yeast two-hybrid system to screen a kidney cDNA library for proteins that interact with the NKCC2 C terminus. One binding partner we identified was SCAMP2 (secretory carrier membrane protein 2). Microscopic confocal imaging and co-immunoprecipitation assays confirmed NKCC2-SCAMP2 interaction in renal cells. SCAMP2 associated also with the structurally related co-transporter NCC, suggesting that the interaction with SCAMP2 is a common feature of sodium-dependent chloride co-transporters. Heterologous expression of SCAMP2 specifically decreased cell surface abundance as well as transport activity of NKCC2 across the plasma membrane. Co-immunolocalization experiments revealed that intracellularly retained NKCC2 co-localizes with SCAMP2 in recycling endosomes. The rate of NKCC2 endocytic retrieval, assessed by the sodium 2-mercaptoethane sulfonate cleavage assay, was not affected by SCAMP2. The surface-biotinylatable fraction of newly inserted NKCC2 in the plasma membrane was reduced by SCAMP2, demonstrating that SCAMP2-induced decrease in surface NKCC2 is due to decreased exocytotic trafficking. Finally, a single amino acid mutation, cysteine 201 to alanine, within the conserved cytoplasmic E peptide of SCAMP2, which is believed to regulate exocytosis, abolished SCAMP2-mediated down-regulation of the co-transporter. Taken together, these data are consistent with a model whereby SCAMP2 regulates NKCC2 transit through recycling endosomes and limits the cell surface targeting of the co-transporter by interfering with its exocytotic trafficking.NKCC2 is an Na-K-2Cl co-transporter protein expressed exclusively in the mammalian kidney, where it provides the major route for sodium/chloride transport across the apical plasma membrane of the thick ascending limb (1). NKCC2 is therefore a pivotal protein in renal function, and exquisitely tight regulation of the apical co-transporter activity is paramount for maintaining extracellular fluid volume and acid-base homeostasis (2). It is the target of loop-diuretics extensively used in the treatment of edematous states and hypertension (3). Furthermore, recent work implicates NKCC2 in the dysfunction of blood pressure regulation, raising new hypotheses regarding the underlying mechanisms behind some types of essential hypertension (4 -7). Most importantly, inactivating mutations of the NKCC2 gene in humans causes Bartter syndrome type 1, a life-threatening kidney disease (8). However, despite this importance, little is known about NKCC2 regulation in renal cells, mainly because of the difficul...

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Section: Discussionsupporting

confidence: 75%

Secretory Carrier Membrane Protein 2 Regulates Exocytic Insertion of NKCC2 into the Cell Membrane

Zaarour

Defontaine

Demaretz

et al. 2011

Journal of Biological Chemistry

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“…It is known that Rab11 regulates trafficking of a variety of other critical proteins and cholesterol, so that other Rab11 effects might be involved. Brain proteins that are known Rab11-dependent cargos include transferrin receptor (iron uptake), brain-enriched Na ϩ /H ϩ exchanger NHE5 (cell volume and pH maintenance) (Diering et al, 2009), glycine transporter GLYT2 (glycine uptake) (Nú ñez et al, 2009), glucose transporter 1 (glucose uptake) (Wieman et al, 2007), and AMPA receptor (long-term potentiation) (Park et al, 2004). The presence of Rab11Q70L in HD neurons may also improve functions related to these proteins.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Rab11-Dependent Trafficking of the Neuronal Glutamate Transporter EAAC1 Causes Oxidative Stress and Cell Death in Huntington's Disease

Li¹,

Valencia²,

Sapp³

et al. 2010

J. Neurosci.

140

122

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Oxidative stress contributes to neurodegeneration in Huntington's disease (HD). However, the origins of oxidative stress in HD remain unclear. Studies in HD transgenic models suggest involvement of mitochondrial dysfunction, which would lead to overproduction of reactive oxygen species (ROS). Impaired mitochondria complexes occur in late stages of HD but not in presymptomatic or early-stage HD patients. Thus, other mechanisms may account for the earliest source of oxidative stress caused by endogenous mutant huntingtin. Here, we report that decreased levels of a major intracellular antioxidant glutathione coincide with accumulation of ROS in primary HD neurons prepared from embryos of HD knock-in mice (HD 140Q/140Q ), which have human huntingtin exon 1 with 140 CAG repeats inserted into the endogenous mouse huntingtin gene. Uptake of extracellular cysteine through the glutamate/cysteine transporter EAAC1 is required for de novo synthesis of glutathione in neurons. We found that, compared with wild-type neurons, HD neurons had lower cell surface levels of EAAC1 and were deficient in taking up cysteine. Constitutive trafficking of EAAC1 from recycling endosomes relies on Rab11 activity, which is defective in the brain of HD 140Q/140Q mice. Enhancement of Rab11 activity by expression of a dominant-active Rab11 mutant in primary HD neurons ameliorated the deficit in cysteine uptake, increased levels of intracellular glutathione, normalized clearance of ROS, and improved neuronal survival. Our data support a novel mechanism for oxidative stress in HD: Rab11 dysfunction slows trafficking of EAAC1 to the cell surface and impairs cysteine uptake, thereby leading to deficient synthesis of glutathione.

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“…It is possible that Ral inhibition contributes to the AKT-inhibition-induced perturbation of NHE1 exocytosis and membrane localization. Further, membrane translocation of another NHE isoform, NHE5, is regulated by SCAMP2 in an Arf6-dependent manner (Diering et al, 2009). As Arf6 is also regulated by AKT signaling, via Grp1 (Li et al, 2012), it would also be relevant to address the possible role of this pathway in PDGF-aa-mediated NHE1 translocation.…”

Section: Discussionmentioning

confidence: 99%

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

Clement

Mally

Stock

et al. 2012

Journal of Cell Science

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SummaryIn fibroblasts, platelet-derived growth factor receptor alpha (PDGFRa) is upregulated during growth arrest and compartmentalized to the primary cilium. PDGF-AA mediated activation of the dimerized ciliary receptor produces a phosphorylation cascade through the PI3K-AKT and MEK1/2-ERK1/2 pathways leading to the activation of the Na + /H + exchanger, NHE1, cytoplasmic alkalinization and actin nucleation at the lamellipodium that supports directional cell migration. We here show that AKT and MEK1/2-ERK1/2-p90 RSK inhibition reduced PDGF-AA-induced cell migration by distinct mechanisms: AKT inhibition reduced NHE1 activity by blocking the translocation of NHE1 to the cell membrane. MEK1/2 inhibition did not affect NHE1 activity but influenced NHE1 localization, causing NHE1 to localize discontinuously in patches along the plasma membrane, rather than preferentially at the lamellipodium. We also provide direct evidence of NHE1 translocation through the cytoplasm to the leading edge. In conclusion, signals initiated at the primary cilium through the PDGFRaa cascade reorganize the cytoskeleton to regulate cell migration differentially through the AKT and the MEK1/2-ERK1/2-p90 RSK pathways. The AKT pathway is necessary for initiation of NHE1 translocation, presumably in vesicles, to the leading edge and for its activation. In contrast, the MEK1/2-ERK1/2-p90 RSK pathway controls the spatial organization of NHE1 translocation and incorporation, and therefore specifies the direction of the leading edge formation.

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Secretory Carrier Membrane Protein 2 Regulates Cell-surface Targeting of Brain-enriched Na+/H+ Exchanger NHE5

Cited by 30 publications

References 78 publications

Secretory Carrier Membrane Protein 2 Regulates Exocytic Insertion of NKCC2 into the Cell Membrane

Secretory Carrier Membrane Protein 2 Regulates Exocytic Insertion of NKCC2 into the Cell Membrane

Aberrant Rab11-Dependent Trafficking of the Neuronal Glutamate Transporter EAAC1 Causes Oxidative Stress and Cell Death in Huntington's Disease

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

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