Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes.
The adenosine monophosphate (AMP)-activated protein kinase (AMPK) has a crucial role in maintaining cellular energy homeostasis. This study shows that human and mouse T lymphocytes express AMPKalpha1 and that this is rapidly activated in response to triggering of the T cell antigen receptor (TCR). TCR stimulation of AMPK was dependent on the adaptors LAT and SLP76 and could be mimicked by the elevation of intracellular Ca(2+) with Ca(2+) ionophores or thapsigargin. AMPK activation was also induced by energy stress and depletion of cellular adenosine triphosphate (ATP). However, TCR and Ca(2+) stimulation of AMPK required the activity of Ca(2+)-calmodulin-dependent protein kinase kinases (CaMKKs), whereas AMPK activation induced by increased AMP/ATP ratios did not. These experiments reveal two distinct pathways for the regulation of AMPK in T lymphocytes. The role of AMPK is to promote ATP conservation and production. The rapid activation of AMPK in response to Ca(2+) signaling in T lymphocytes thus reveals that TCR triggering is linked to an evolutionally conserved serine kinase that regulates energy metabolism. Moreover, AMPK does not just react to cellular energy depletion but also anticipates it.
Tamás
Peter
P
Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
Hawley
Simon A
SA
Clarke
Rosemary G
RG
Mustard
Kirsty J
KJ
Green
Kevin
K
Hardie
D Grahame
DG
Cantrell
Doreen A
DA
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053644:Naphthalimides; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009097:Multienzyme Complexes; D053644:Naphthalimides; D011948:Receptors, Antigen, T-Cell; C458525:STO 609; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium