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J. Cell Biol.,
Volume 140, Number 5, March 9, 1998 1199-1209
The Netherlands Cancer Institute, Division of Cellular Biochemistry, 1066 CX Amsterdam, The Netherlands
Gap junctions mediate cell-cell communication in almost all tissues, but little is known about their
regulation by physiological stimuli. Using a novel single-electrode technique, together with dye coupling
studies, we show that in cells expressing gap junction protein connexin43, cell-cell communication is rapidly
disrupted by G protein-coupled receptor agonists, notably lysophosphatidic acid, thrombin, and neuropeptides. In the continuous presence of agonist, junctional
communication fully recovers within 1-2 h of receptor
stimulation. In contrast, a desensitization-defective G
protein-coupled receptor mediates prolonged uncoupling, indicating that recovery of communication is controlled, at least in part, by receptor desensitization. Agonist-induced gap junction closure consistently follows
inositol lipid breakdown and membrane depolarization and coincides with Rho-mediated cytoskeletal remodeling. However, we find that gap junction closure is independent of Ca2+, protein kinase C, mitogen-activated
protein kinase, or membrane potential, and requires
neither Rho nor Ras activation. Gap junction closure is
prevented by tyrphostins, by dominant-negative c-Src, and in Src-deficient cells. Thus, G protein-coupled receptors use a Src tyrosine kinase pathway to transiently
inhibit connexin43-based cell-cell communication.
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