AMP-activated protein kinase - not just an energy sensor

Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy. In this article, we discuss a few interesting recent developments in the AMPK field. Firstly, we review recent findings on the canonical pathway by which AMPK is regulated by adenine nucleotides. Secondly, AMPK is now known to be activated in mammalian cells by glucose starvation by a mechanism that occurs in the absence of changes in adenine nucleotides, involving the formation of complexes with Axin and LKB1 on the surface of the lysosome. Thirdly, in addition to containing the nucleotide-binding sites on the γ subunits, AMPK heterotrimers contain a site for binding of allosteric activators termed the allosteric drug and metabolite (ADaM) site. A large number of synthetic activators, some of which show promise as hypoglycaemic agents in pre-clinical studies, have now been shown to bind there. Fourthly, some kinase inhibitors paradoxically activate AMPK, including one (SU6656) that binds in the catalytic site. Finally, although downstream targets originally identified for AMPK were mainly concerned with metabolism, recently identified targets have roles in such diverse areas as mitochondrial fission, integrity of epithelial cell layers, and angiogenesis

Effects of recruitment maneuver and PEEP on respiratory mechanics and transpulmonary pressure during laparoscopic surgery

Background: We tested the hypothesis that during laparoscopic surgery, Trendelenburg position and pneumoperitoneum (PnP) may worsen chest wall elastance (ECW), concomitantly decreasing transpulmonary pressure (PL) and that a protective ventilator strategy applied after PnP induction, by increasing PL would result in alveolar recruitment and improvement in respiratory mechanics and gas exchange. Methods: In twenty-nine consecutive patients an open lung strategy (OLS) consisting in a recruiting manoeuvre (RM) followed by PEEP 5cmH20 maintained until the end of surgery was applied after PnP induction. Respiratory mechanics, gas exchange, blood pressure (BP) and cardiac index (CI) were measured before (TBSL) and after PnP with zero PEEP (TpreOLS), after RM with PEEP (TpostOLS), after peritoneum desufflation with PEEP (Tend). Results: Esophageal pressure was used for partitioning respiratory mechanics between lung and chest wall (data are mean +-standard deviation, SD): on TpreOLS, ECW and the elastance of the lung (EL) increased (respectively 8.2±0.9cmH2O/L vs 6.2±1.2cmH2O/L on TBSL, p=0.00016; and 11.69±1.68cmH2O/L vs 9.61±1.52cmH2O/L on TBSL; p=0.0007). After OLS both ECW and EL decreased (5.2±1.2cmH2O/L and 8.62±1.03cmH2O/L respectively; both p=0.00015 vs TpreOLS ), and PaO2/FiO2 improved (491+107 vs 425±97 on TpreOLS; p=0.008) remaining stable thereafter. Recruited volume (computed as the difference in lung volume for the same static airway pressure), was 194±80ml. PplatRS remained stable while inspiratory transpulmonary pressure (PplatL) increased (11.65+1.37 cmH2O vs 9.21+2.03 on TpreOLS; p=0.007). All respiratory mechanics parameters remained stable after abdominal desufflation. Hemodynamic parameters remained stable throughout the study. Conclusions: In patients submitted to laparoscopic surgery in Trendelenburg position, an OLS applied after PnP induction increased PL and led to alveolar recruitment and improvement of ECW, EL and gas exchange