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

J Cell Biol. 2007 Jun 4;177(5):881-91. doi: 10.1083/jcb.200610144. Epub 2007 May 29.


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]P(2)) from the plasma membrane. Knockdown of phospholipase Cbeta3 (PLCbeta3) inhibits PtdIns(4,5)P(2) hydrolysis and keeps Cx43 channels open after receptor activation. Using a translocatable 5-phosphatase, we show that PtdIns(4,5)P(2) depletion is sufficient to close Cx43 channels. When PtdIns(4,5)P(2) 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 PLCbeta3 via its third PDZ domain. ZO-1 is essential for PtdIns(4,5)P(2)-hydrolyzing receptors to inhibit cell-cell communication, but not for receptor-PLC coupling. Our results show that PtdIns(4,5)P(2) is a key regulator of Cx43 channel function, with no role for other second messengers, and suggest that ZO-1 assembles PLCbeta3 and Cx43 into a signaling complex to allow regulation of cell-cell communication by localized changes in PtdIns(4,5)P(2).

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication*
  • Connexin 43 / metabolism*
  • Gap Junctions / metabolism*
  • Humans
  • Hydrolysis
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Mice
  • Models, Neurological
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phospholipase C beta
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Signal Transduction
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / chemistry
  • Type C Phospholipases / metabolism
  • Zonula Occludens-1 Protein


  • Connexin 43
  • Isoenzymes
  • Membrane Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphoproteins
  • TJP1 protein, human
  • Tjp1 protein, mouse
  • Tjp1 protein, rat
  • Zonula Occludens-1 Protein
  • Type C Phospholipases
  • Phospholipase C beta