γ-adducin stimulates the thiazide-sensitive NaCl cotransporter

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Abstract

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. 22Na+ 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. Copyright © 2011 by the American Society of Nephrology.

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Dimke, H., San-Cristobal, P., De Graaf, M., Lenders, J. W., Deinum, J., Hoenderop, J. G. J., & Bindels, R. J. M. (2011). γ-adducin stimulates the thiazide-sensitive NaCl cotransporter. Journal of the American Society of Nephrology, 22(3), 508–517. https://doi.org/10.1681/ASN.2010060606

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