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

¹ Division of Cellular Biochemistry, Centre for Biomedical Genetics, and ² Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
³ Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Correspondence to Wouter H. Moolenaar: w.moolenaar{at}nki.nl; or Kees Jalink: k.jalink{at}nki.nl

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 Cß3 (PLCß3) 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 PLCß3 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 PLCß3 and Cx43 into a signaling complex to allow regulation of cell–cell communication by localized changes in PtdIns(4,5)P₂.

F.R. Postma's present address is Department of Neurobiology, Harvard Medical School, Boston, MA 02115.

P. Várnai's present address is Department of Physiology, Semmelweis University, Faculty of Medicine, 1085 Budapest, Hungary.

Abbreviations used in this paper: Cx43, connexin43; FKB12, FK506 binding protein 12; FRET, fluorescence resonance energy transfer; GPCR, G protein–coupled receptor; IP₃, inositol-1,4,5-trisphosphate; LY, Lucifer yellow; mRFP, monomeric red fluorescent protein; PH, pleckstrin homology; PIP5K, PtdIns(4)P 5-kinase; PtdIns(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; shRNA, short hairpin RNA; TRP, thrombin receptor-activating peptide; ZO-1, zona occludens 1.

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