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MoolenaarJCB2007 - Published JCB ARTICLE Regulation of...

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T H E J O U R N A L O F C E L L B I O L O G Y JCB: ARTICLE The Journal of Cell Biology, Vol. 177, No. 5, June 04, 2007 881–891 http://www.jcb.org/cgi/doi/10.1083/jcb.200610144 JCB 881 Introduction Communication between adjacent cells through gap junctions occurs in nearly every tissue and is fundamental to coordinated cell behavior. Gap junctions are composed of connexins, con- sisting of an intracellular N terminus, four transmembrane do- mains, and a cytosolic C-terminal tail. Six connexins oligomerize into a pore-forming connexon, and alignment of two connex- ons in apposing cell membranes forms a gap junction channel. These channels allow direct cell-to-cell diffusion of ions and small molecules ( < 1–2 kD), including nutrients, metabolites, second messengers, and peptides, without transit through the extracellular space (Goodenough et al., 1996; Harris, 2001; Saez et al., 2003). Gap junctions play important roles in normal tissue function and organ development (Reaume et al., 1995; Sohl and Willecke, 2004; Wei et al., 2004) and have been impli- cated in a great diversity of biological processes, notably, elec- trical synchronization of excitable cells, energy metabolism, growth control, wound repair, tumor cell invasion, and antigen cross-presentation (Kwak et al., 2001; Qiu et al., 2003; Mesnil et al., 2005; Oliveira et al., 2005; Neijssen et al., 2005; Bernstein and Morley, 2006; Mori et al., 2006). The importance of gap junctions is highlighted by the discovery that mutations in con- nexins underlie a variety of genetic diseases, including periph- eral neuropathy, skin disorders, and deafness (Gerido and White, 2004; Wei et al., 2004). Connexin43 (Cx43) is the most abundant and best-studied mammalian connexin. Cx43-based gap junctional communica- tion is of a particular interest because it is regulated by both physio- logical and pathophysiological stimuli. In particular, Cx43-based Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate Leonie van Zeijl, 1 Bas Ponsioen, 1,2 Ben N.G. Giepmans, 1 Aafke Ariaens, 1 Friso R. Postma, 1 Péter Várnai, 3 Tamas Balla, 3 Nullin Divecha, 1 Kees Jalink, 2 and Wouter H. Moolenaar 1 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 C ell–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 inhib- ited by depletion of phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P 2 ) from the plasma membrane. Knockdown of phospholipase C β 3 (PLC β 3) inhibits PtdIns(4,5)P 2 hydrolysis and keeps Cx43 channels open after recep- tor 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.
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