Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 10, pp 2121–2140 | Cite as

Homodimeric anoctamin-1, but not homodimeric anoctamin-6, is activated by calcium increases mediated by the P2Y1 and P2X7 receptors

  • Michaela Stolz
  • Manuela Klapperstück
  • Thomas Kendzierski
  • Silvia Detro-dassen
  • Anna Panning
  • Günther Schmalzing
  • Fritz Markwardt
Ion channels, receptors and transporters

Abstract

The P2X7 receptor (P2X7R) is a ligand-gated ion channel that conducts Na+, K+, and Ca2+ when activated by extracellular ATP. In various cell types, such as secretory epithelia, the P2X7R is co-expressed with Ca2+-dependent Cl channels of the TMEM16/anoctamin family. Here, we studied whether the P2X7R and TMEM16A/anoctamin-1 (Ano1) or TMEM16F/anoctamin-6 (Ano6) interact functionally and physically, using oocytes of Xenopus laevis and Ambystoma mexicanum (Axolotl) for heterologous expression. As a control, we co-expressed anoctamin-1 with the P2Y1 receptor (P2Y1R), which induces the release of Ca2+ from intracellular stores via activating phospholipase C through coupling to Gαq. We found that co-expression of anoctamin-1 with the P2Y1R resulted in a small transient increase in Cl conductance in response to ATP. Co-expression of anoctamin-1 with the P2X7R resulted in a large sustained increase in Cl conductance via Ca2+ influx through the ATP-opened P2X7R in Xenopus and in Axolotl oocytes, which lack endogenous Ca2+-dependent Cl channels. P2Y1R- or P2X7R-mediated stimulation of Ano1 was primarily functional, as demonstrated by the absence of a physically stable interaction between Ano1 and the P2X7R. In the pancreatic cell line AsPC-1, we found the same functional Ca2+-dependent interaction of P2X7R and Ano1. The P2X7R-mediated sustained activation of Ano1 may be physiologically relevant to the time course of stimulus-secretion coupling in secretory epithelia. No such increase in Cl conductance could be elicited by activating the P2X7 receptor in either Xenopus oocytes or Axolotl oocytes co-expressing Ano6. The lack of function of Ano6 can, at least in part, be explained by its poor cell-surface expression, resulting from a relatively inefficient exit of the homodimeric Ano6 from the endoplasmic reticulum.

Keywords

Anoctamin-1 Anoctamin-6 P2X7 receptor Quaternary structure Intracellular Ca2+ 

Supplementary material

424_2015_1687_Fig13_ESM.gif (35 kb)
Fig. S1

ADP-induced mP2Y1-dependent activation of mANO1. Experiments were performed in Ca-ORi using the same protocol as described in the legend to Fig. 3b (GIF 35 kb)

424_2015_1687_MOESM1_ESM.tif (903 kb)
High-resolution image (TIFF 903 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michaela Stolz
    • 1
  • Manuela Klapperstück
    • 2
  • Thomas Kendzierski
    • 2
  • Silvia Detro-dassen
    • 1
  • Anna Panning
    • 1
  • Günther Schmalzing
    • 1
  • Fritz Markwardt
    • 2
  1. 1.Molecular PharmacologyRWTH Aachen UniversityAachenGermany
  2. 2.Julius-Bernstein-Institute for PhysiologyMartin-Luther-University Halle-WittenbergHalle/SaaleGermany

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