AMPK in the control of hepatic glucagon signalling and protein synthesis

Johanns, Manuel [UCL]

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis via effects on multiple downstream targets. Firstly, we discovered the mechanism by which AMPK antagonizes hepatic glucagon signalling, which is elevated in type 2 diabetes and participates in the establishment of hyperglycaemia. We identified cyclic nucleotide phosphodiesterase 4B (PDE4B) as a novel AMPK substrate in liver. AMPK phosphorylates PDE4B at several sites leading to its activation, decreasing cyclic AMP levels and downstream PKA signalling induced by glucagon. Secondly, we clarified how AMPK activation leads to decreased protein synthesis. It is known that AMPK downregulates protein translation by inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of elongation factor 2 kinase (eEF2K), a kinase that phosphorylates and inhibits the essential translation factor eEF2. We showed how eEF2K is controlled by cytosolic Ca2+, mTORC1 and AMPK. We identified a new phosphorylation site (Ser491/Ser492) crucial for eEF2K activation by AMPK.