A central role of connexin 43 in hypoxic preconditioning.
Preconditioning is an endogenous mechanism in which a nonlethal exposure increases cellular resistance to subsequent additional severe injury. Here we show that connexin 43 (Cx43) plays a key role in protection afforded by preconditioning. Cx43 null mice were insensitive to hypoxic preconditioning, whereas wild-type littermate mice exhibited a significant reduction in infarct volume after occlusion of the middle cerebral artery. In cultures, Cx43-deficient cells responded to preconditioning only after exogenous expression of Cx43, and protection was attenuated by small interference RNA or by channel blockers. Our observations indicate that preconditioning reduced degradation of Cx43, resulting in a marked increase in the number of plasma membrane Cx43 hemichannels. Consequently, efflux of ATP through hemichannels led to accumulation of its catabolic product adenosine, a potent neuroprotective agent. Thus, adaptive modulation of Cx43 can offset environmental stress by adenosine-mediated elevation of cellular resistance.
Lin
Jane H-C
JH
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA. jane_lin@nymc.edu
Lou
Nanhong
N
Kang
Ning
N
Takano
Takahiro
T
Hu
Furong
F
Han
Xiaoning
X
Xu
Qiwu
Q
Lovatt
Ditte
D
Torres
Arnulfo
A
Willecke
Klaus
K
Yang
Jay
J
Kang
Jian
J
Nedergaard
Maiken
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D018031:Connexin 43 / Q000172:deficiency / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019194:Ischemic Preconditioning; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D013997:Time Factors; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
D018031:Connexin 43; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide