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

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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.

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Acknowledgments

We would like to thank the Deutsche Forschungsgemeinschaft (Ma1581/15-3; Schm536/9-3) for their financial support. We would also like to thank GlaxoSmithKline for their permission to use the monoclonal antibody against the hP2X7R ectodomain, Prof. Dr. Friedrich Koch-Nolte of University Medical Center, Hamburg for providing us with the corresponding hybridoma cell line, and Prof. Dr. Barbara Seliger, Institute for Medical Immunology of the Martin-Luther-University Halle for providing us the AsPC-1 cell line.

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The experiments comply with the current laws of Germany.

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  1. Molecular Pharmacology, RWTH Aachen University, Wendlingweg 2, D-52074, Aachen, Germany

    Michaela Stolz, Silvia Detro-dassen, Anna Panning & Günther Schmalzing

  2. Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 6, D-06097, Halle/Saale, Germany

    Manuela Klapperstück, Thomas Kendzierski & Fritz Markwardt

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  1. Michaela Stolz
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Günther Schmalzing and Fritz Markwardt share senior authorship.

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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)

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Stolz, M., Klapperstück, M., Kendzierski, T. et al. Homodimeric anoctamin-1, but not homodimeric anoctamin-6, is activated by calcium increases mediated by the P2Y1 and P2X7 receptors. Pflugers Arch - Eur J Physiol 467, 2121–2140 (2015). https://doi.org/10.1007/s00424-015-1687-3

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  • DOI: https://doi.org/10.1007/s00424-015-1687-3

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