Muscarinic receptor activation of AMP-activated protein kinase inhibits orexigenic neuropeptide mRNA expression.
AMP-activated protein kinase (AMPK) plays a crucial role in both cellular and whole body energy homeostasis. Here we demonstrate that the muscarinic receptor agonist carbachol activates AMPKalpha1-containing complexes in the human SH-SY5Y cell line via a mechanism specific for the AMPK upstream kinase, Ca(2+)/calmodulin-dependent protein kinase kinase beta. Activation of AMPK inhibits mRNA expression of the orexigenic neuropeptides Agouti-related peptide and melanin-concentrating hormone but surprisingly has no effect on neuropeptide Y mRNA, a neuropeptide previously shown to be regulated by AMPK. Rather than restoring mRNA levels to baseline, pharmacological inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase beta or AMPK greatly increases Agouti-related peptide and melanin-concentrating hormone mRNA expression. These data support a hypothesis that modulating basal AMPK activity in the hypothalamus is essential for maintaining tight regulation of pathways contributing to food intake.
Thornton
Claire
C
Medical Research Council (MRC) Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London W12 0NN, United Kingdom. claire.thornton@imperial.ac.uk
Sardini
Alessandro
A
Carling
David
D
D055372:AMP-Activated Protein Kinases; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D004435:Eating; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*
D009097:Multienzyme Complexes; D009479:Neuropeptides; D009711:Nucleotides; D010455:Peptides; D012333:RNA, Messenger; D011976:Receptors, Muscarinic; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D002118:Calcium