Transduction of cell survival signals by connexin-43 hemichannels.
Bisphosphonates, drugs used widely in the treatment of bone diseases, prevent osteoblast and osteocyte apoptosis by a mechanism involving extracellular signal-regulated kinase (ERK) activation. We report herein that hexameric connexin (Cx)-43 hemichannels, but not gap junctions, are the essential transducers of the ERK-activating/anti-apoptotic effects of bisphosphonates. Transfection of Cx-43, but not other Cxs, into Cx-43 naive cells confers de novo responsiveness to the drugs. The signal-transducing property of Cx-43 requires the pore forming as well as the C-terminal domains of the protein, the activation of both Src and ERK kinases, and the SH2 and SH3 domains of Src. This evidence adds Cx-43 to the list of transmembrane proteins capable of transducing survival signals in response to extracellular cues and raises the possibility that it may serve in this capacity for endogenously produced molecules or even other drugs.
Plotkin
Lilian I
LI
Division of Endocrinology and Metabolism, the Center for Osteoporosis and Metabolic Bone Diseases, and the Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Manolagas
Stavros C
SC
Bellido
Teresita
T
D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D018031:Connexin 43 / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010011:Osteocytes / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D018909:src Homology Domains
D018031:Connexin 43; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases; D019386:Alendronate