Purinergic control of AMPK activation by ATP released through connexin 43 hemichannels - pivotal roles in hemichannel-mediated cell injury.
Connexin hemichannels regulate many cell functions. However, the molecular mechanisms involved remain elusive. Hemichannel opening causes loss of ATP, we therefore speculated a potential role for AMPK in the biological actions of hemichannels. Activation of hemichannels by removal of extracellular Ca(2+) led to an efflux of ATP and a weak activation of AMPK. Unexpectedly, dysfunction of hemichannels markedly potentiated AMPK activation, which was reproduced by promotion of extracellular ATP degradation or inhibition of P2 purinoceptors but counteracted by exogenous ATP. Further analysis revealed that ATP induced a purinoceptor-dependent activation of Akt and mTOR. Suppression of Akt or mTOR augmented AMPK activation, whereas activation of Akt by transfection of cells with myristoylated Akt, a constitutively active form of Akt, abolished AMPK activation. In a pathological model of hemichannel opening triggered by Cd(2+), disclosure of hemichannels similarly enhanced AMPK activity, which protected cells from Cd(2+)-induced cell injury through suppression of mTOR. In summary, our data point to a channel-mediated mechanism for the regulation of AMPK through a purinergic signaling pathway. Furthermore, we define AMPK as a pivotal molecule that underlies the regulatory effects of hemichannels on cell survival.
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Yuan
Y
Chi
Kun
K
Gao
Kai
K
Li
Shotaro
S
Nakajima
Satoru
S
Kira
Masayuki
M
Takeda
Jian
J
Yao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D018031:Connexin 43 / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism*; D013552:Swine
D018031:Connexin 43; D011983:Receptors, Purinergic; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D002118:Calcium
AMPK; ATP; Cell survival; Hemichannels; Purinergic signaling