title: Transfer of IP₃ through gap junctions is critical, but not sufficient, for the spread of apoptosis.
abstract: Decades of research have indicated that gap junction channels contribute to the propagation of apoptosis between neighboring cells. Inositol 1,4,5-trisphosphate (IP₃) has been proposed as the responsible molecule conveying the apoptotic message, although conclusive results are still missing. We investigated the role of IP₃ in a model of gap junction-mediated spreading of cytochrome C-induced apoptosis. We used targeted loading of high-molecular-weight agents interfering with the IP₃ signaling cascade in the apoptosis trigger zone and cell death communication zone of C6-glioma cells heterologously expressing connexin (Cx)43 or Cx26. Blocking IP₃ receptors or stimulating IP₃ degradation both diminished the propagation of apoptosis. Apoptosis spread was also reduced in cells expressing mutant Cx26, which forms gap junctions with an impaired IP₃ permeability. However, IP₃ by itself was not able to induce cell death, but only potentiated cell death propagation when the apoptosis trigger was applied. We conclude that IP₃ is a key necessary messenger for communicating apoptotic cell death via gap junctions, but needs to team up with other factors to become a fully pro-apoptotic messenger.
authors: Department of Basic Medical Sciences - Physiology group, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium.
authors: E
authors: E
authors: Decrock
authors: D V
authors: DV
authors: Krysko
authors: M
authors: M
authors: Vinken
authors: A
authors: A
authors: Kaczmarek
authors: G
authors: G
authors: Crispino
authors: M
authors: M
authors: Bol
authors: N
authors: N
authors: Wang
authors: M
authors: M
authors: De Bock
authors: E
authors: E
authors: De Vuyst
authors: C C
authors: CC
authors: Naus
authors: V
authors: V
authors: Rogiers
authors: P
authors: P
authors: Vandenabeele
authors: C
authors: C
authors: Erneux
authors: F
authors: F
authors: Mammano
authors: G
authors: G
authors: Bultynck
authors: L
authors: L
authors: Leybaert
mesh_terms: D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D002463:Cell Membrane Permeability; D000072259:Connexin 26; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D018031:Connexin 43; D017630:Connexins; C000607044:Gjb2 protein, rat; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000072259:Connexin 26; D015544:Inositol 1,4,5-Trisphosphate; D045304:Cytochromes c