title: AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3.
abstract: AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimidazole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serine-phosphorylation of its substrates, glycogen synthase kinase-3alpha/beta (GSK3alpha/beta). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factor-induced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
authors.forename: Taj D
authors.initials: TD
authors.lastname: King
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D010629:Phenformin / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000502:physiology; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D009097:Multienzyme Complexes; D011976:Receptors, Muscarinic; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D007334:Insulin-Like Growth Factor I; D002217:Carbachol; D010629:Phenformin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide