Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate

Leonie Van Zeijl, Bas Ponsioen, Ben N.G. Giepmans, Aafke Ariaens, Friso R. Postma, Péter Várnai, Tamas Balla, Nullin Divecha, Kees Jalink, Wouter H. Moolenaar

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Cell-cell communication through connexin43 (Cx43)-based gap junction channels is rapidly inhibited upon activation of various G protein-coupled receptors; however, the mechanism is unknown. We show that Cx43-based cell-cell communication is inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) from the plasma membrane. Knockdown of phospholipase Cβ3 (PLCβ3) inhibits PtdIns(4,5)P2 hydrolysis and keeps Cx43 channels open after receptor activation. Using a translocatable 5-phosphatase, we show that PtdIns(4,5)P2 depletion is sufficient to close Cx43 channels. When PtdIns(4,5)P2 is overproduced by PtdIns(4)P 5-kinase, Cx43 channel closure is impaired. We find that the Cx43 binding partner zona occludens 1 (ZO-1) interacts with PLCβ3 via its third PDZ domain. ZO-1 is essential for PtdIns(4,5)P2-hydrolyzing receptors to inhibit cell-cell communication, but not for receptor-PLC coupling. Our results show that PtdIns(4,5)P2 is a key regulator of Cx43 channel function, with no role for other second messengers, and suggest that ZO-1 assembles PLCβ3 and Cx43 into a signaling complex to allow regulation of cell-cell communication by localized changes in PtdIns(4,5)P2.

Original languageEnglish
Pages (from-to)881-891
Number of pages11
JournalJournal of Cell Biology
Issue number5
Publication statusPublished - Jun 4 2007


ASJC Scopus subject areas

  • Cell Biology

Cite this

Van Zeijl, L., Ponsioen, B., Giepmans, B. N. G., Ariaens, A., Postma, F. R., Várnai, P., Balla, T., Divecha, N., Jalink, K., & Moolenaar, W. H. (2007). Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate. Journal of Cell Biology, 177(5), 881-891.