title: Chronic high cytosolic calcium decreases AICAR-induced AMPK activity via calcium/calmodulin activated protein kinase II signaling cascade.
abstract: Calcium is important for muscle contraction and controls many cellular processes. Although there is evidence that calcium-mediated signals regulate AMP-activated protein kinase (AMPK) activity, the molecular mechanisms by which calcium regulates AMPK are poorly understood. To compare the function of sustained vs. intermittent calcium oscillations on AMPK activity and define specific signals in this pathway, we administered mice with aminoimidazole-carboxamide-ribonucleotide (AICAR) and caffeine with or without dantrolene. AMPK activity was increased by 10 d AICAR treatment (P < 0.01). Ten day caffeine treatment decreased AICAR-induced AMPK activity to control level. This repressed AMPK activity was blocked by dantrolene. Different calcium frequencies were simulated in C2C12 myotubes by alternating media containing caffeine and dantrolene. Intermittent calcium oscillation increased AMPK activity compared to control (P < 0.05), whereas sustained calcium oscillation decreases AICAR-induced AMPK activity to control level. This result suggests a biphasic control of AMPK activity by calcium. Knockdown of CaMKII expression by short-hairpin RNA resulted in increased AMPK phosphorylation by AICAR even in the presence of caffeine. These data show different calcium oscillations elicit distinct responses in muscle cells suggesting that the negative effects of chronic calcium treatment on AMPK activity is partly mediated through the CaMKII signals.
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: T L
authors.initials: TL
authors.lastname: Scheffler
authors.forename: D E
authors.initials: DE
authors.lastname: Gerrard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D002110:Caffeine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D003620:Dantrolene; D002118:Calcium