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© The Rockefeller University Press, 0021-9525/1998//1199 $5.00
The Journal of Cell Biology, Volume 140, Number 5, , 1998 1199-1209

Article

Acute loss of Cell–Cell Communication Caused by G Protein–coupled Receptors: A Critical Role for c-Src



Friso R. Postma, Trudi Hengeveld, Jacqueline Alblas, Ben N.G. Giepmans, Gerben C.M. Zondag, Kees Jalink, and Wouter H. Moolenaar

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.

Abbreviations used in this paper: Cx43, connexin43; Et, endothelin; LPA, lysophosphatidic acid; LY, Lucifer yellow; MAP, mitogen-activated protein; NKA, neurokinin A; PKC, protein kinase C; PTX, pertussis toxin; TRP, thrombin receptor–activating peptide.

Jacqueline Alblas' current address is Department of Pulmonary Diseases, University Hospital Utrecht, 3584 CX Utrecht, The Netherlands.

Address all correspondence to Wouter H. Moolenaar, The Netherlands Cancer Institute, Division of Cellular Biochemistry, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: +31-20-512 1971. Fax: +31-20-512 1989. E-mail: wmoolen{at}nki.nl


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