γ-Adducin stimulates the thiazide-sensitive NaCl cotransporter

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  • Henrik Anthony Dimke, Denmark
  • Pedro San-Cristobal
  • ,
  • Mark de Graaf
  • ,
  • Jacques W Lenders
  • ,
  • Jaap Deinum
  • ,
  • Joost G J Hoenderop
  • ,
  • René J M Bindels
The thiazide-sensitive NaCl cotransporter (NCC) plays a key role in renal salt reabsorption and the determination of systemic BP, but the molecular mechanisms governing the regulation of NCC are not completely understood. Here, through pull-down experiments coupled to mass spectrometry, we found that γ-adducin interacts with the NCC transporter. γ-Adducin colocalized with NCC to the distal convoluted tubule. (22)Na(+) uptake experiments in the Xenopus laevis oocyte showed that γ-adducin stimulated NCC activity in a dose-dependent manner, an effect that occurred upstream from With No Lysine (WNK) 4 kinase. The binding site of γ-adducin mapped to the N terminus of NCC and encompassed three previously reported phosphorylation sites. Supporting this site of interaction, competition with the N-terminal domain of NCC abolished the stimulatory effect of γ-adducin on the transporter. γ-Adducin failed to increase NCC activity when these phosphorylation sites were constitutively inactive or active. In addition, γ-adducin bound only to the dephosphorylated N terminus of NCC. Taken together, our observations suggest that γ-adducin dynamically regulates NCC, likely by amending the phosphorylation state, and consequently the activity, of the transporter. These data suggest that γ-adducin may influence BP homeostasis by modulating renal NaCl transport.
Original languageEnglish
JournalJournal of the American Society of Nephrology
Volume22
Issue3
Pages (from-to)508-17
Number of pages10
ISSN1046-6673
DOIs
Publication statusPublished - 2011

    Research areas

  • Absorption, Animals, Blood Pressure, Calmodulin-Binding Proteins, Dose-Response Relationship, Drug, Female, Humans, Kidney Tubules, Distal, Models, Animal, Oocytes, Phosphorylation, Sodium Chloride, Sodium Chloride Symporters, Xenopus laevis

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