Abstract
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.
Bibliography
van Zeijl, L., Ponsioen, B., Giepmans, B. N. G., Ariaens, A., Postma, F. R., VaÌrnai, P., Balla, T., Divecha, N., Jalink, K., & Moolenaar, W. H. (2007). Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate. The Journal of Cell Biology, 177(5), 881â891.
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Dates
Type | When |
---|---|
Created | 18 years, 2 months ago (May 29, 2007, 9:34 p.m.) |
Deposited | 2 years ago (July 29, 2023, 4:58 a.m.) |
Indexed | 4 months ago (April 22, 2025, 4:10 a.m.) |
Issued | 18 years, 2 months ago (May 29, 2007) |
Published | 18 years, 2 months ago (May 29, 2007) |
Published Online | 18 years, 2 months ago (May 29, 2007) |
Published Print | 18 years, 2 months ago (June 4, 2007) |
@article{van_Zeijl_2007, title={Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate}, volume={177}, ISSN={0021-9525}, url={http://dx.doi.org/10.1083/jcb.200610144}, DOI={10.1083/jcb.200610144}, number={5}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={van Zeijl, Leonie and Ponsioen, Bas and Giepmans, Ben N.G. and Ariaens, Aafke and Postma, Friso R. and Várnai, Péter and Balla, Tamas and Divecha, Nullin and Jalink, Kees and Moolenaar, Wouter H.}, year={2007}, month=may, pages={881–891} }