The Na+/K+-ATPase and the amyloid-beta peptide aβ1-40 control the cellular distribution, abundance and activity of TRPC6 channels

Sylvain Chauvet, Marielle Boonen, Mireille Chevallet, Louis Jarvis, Addis Abebe, Mohamed Benharouga, Peter Faller, Michel Jadot, Alexandre Bouron

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Abstract

The Na(+)/K(+)-ATPase interacts with the non-selective cation channels TRPC6 but the functional consequences of this association are unknown. Experiments performed with HEK cells over-expressing TRPC6 channels showed that inhibiting the activity of the Na(+)/K(+)-ATPase with ouabain reduced the amount of TRPC6 proteins and depressed Ca(2+) entry through TRPC6. This effect, not mimicked by membrane depolarization with KCl, was abolished by sucrose and bafilomycin-A, and was partially sensitive to the intracellular Ca(2+) chelator BAPTA/AM. Biotinylation and subcellular fractionation experiments showed that ouabain caused a multifaceted redistribution of TRPC6 to the plasma membrane and to an endo/lysosomal compartment where they were degraded. The amyloid beta peptide Aβ1-40, another inhibitor of the Na(+)/K(+)-ATPase, but not the shorter peptide Aβ1-16, reduced TRPC6 protein levels and depressed TRPC6-mediated responses. In cortical neurons from embryonic mice, ouabain, veratridine (an opener of voltage-gated Na(+) channel), and Aβ1-40 reduced TRPC6-mediated Ca(2+) responses whereas Aβ1-16 was ineffective. Furthermore, when Aβ1-40 was co-added together with zinc acetate it could no longer control TRPC6 activity. Altogether, this work shows the existence of a functional coupling between the Na(+)/K(+)-ATPase and TRPC6. It also suggests that the abundance, distribution and activity of TRPC6 can be regulated by cardiotonic steroids like ouabain and the naturally occurring peptide Aβ1-40 which underlines the pathophysiological significance of these processes.

Original languageEnglish
Article number17657
Pages (from-to)2957-2965
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1853
Issue number11
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

  • Aβ peptides
  • Lysosomes
  • Na/K pump
  • Neurons
  • Trafficking
  • TRPC6

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