Given that hypoxia likely triggers an increase in cellular AMP levels, it seems possible that the AMP-activated protein kinase (AMPK) may play a role in regulating the activity of 02-sensing cells. AMPK is a multi-substrate serine/threonine kinase, which acts as a metabolic sensor and modulates many aspects of cell metabolism in eukaryotes (37,47). AMPK effectively detects metabolic stress through changes in the local ATP:AMP ratio, and may be activated by vigorous exercise, nutrient starvation and hypoxia (37,47). AMPK is an a,|3,Y heterotrimer, and its activity is increased 2-4 fold by the association of AMP with an allosteric site. However, the AMPK activity is also regulated by an upstream kinase, namely AMPK kinase (39). AMPK kinase is also activated by AMP and regulates AMPK by phosphorylation of Thrl72 within the activation loop of the AMPKasubunit(37, 47). In response to hypoxia, AMPK acts to maintain ATP levels with the minimum amount of 02utilization. AMPK does so by inducing the expression and subsequent translocation of GLUT to the plasma membrane (43, 49, 75), by accelerating glycolysis via phosphorylation of phosphofructokinase (59), and by inhibiting creatine kinase (71). These properties are consistent with the likely effects of hypoxia on pulmonary artery smooth muscle cell metabolism. AMPK kinase and AMPK, respectively, may therefore act as the "primary metabolic sensors" and "primary effectors" in 02-sensing cells, with the activity of AMPK kinase/AMPK determined by the "metabolic setting" under normoxic and hypoxic conditions, respectively.
Given that AMPK targets an array ofproteins including ion channels (35), it is possible that AMP-dependent activation of AMPK kinase and AMPK, respectively, in pulmonary artery smooth muscle may also regulate Ca2+ signaling. Thus, phosphorylation of ADP-ribosyl cyclase by AMPK could elicit a consequent increase in cADPR-dependent Ca signaling by hypoxia. Furthermore, AMPK activation could also, by a direct or indirect action, inhibit potassium channel activity in the plasma membrane and SERCA activity in the peripheral SR proximal to the plasma membrane.
Figure 5. Proposed mechanism for the regulation of cell metabolism and cADPR accumulation by hypoxia. Hypoxia inhibits mitochondrial oxidative phosphorylation, triggering a fall in ATP levels and a consequent rise in AMP levels via the adenylate kinase reaction. This leads to the activation of the primary "metabolic sensors" and "primary effectors", namely AMPKK and AMPK, respectively. AMPK then accelerates glucose transport, glycolysis, and inhibits creatine kinase in an effort to maintain ATP levels at the primary sites of utilization. In addition, however, AMPK may activate ADP-ribosyl cyclase and cADPR accumulation, and inhibit SERCA activity in the peripheral SR proximal to the plasma membrane. AMPK, AMP activated kinase; AMPKK, AMP kinase kinase; GLUT, glucose transporter; AC, ADP-ribosyl cyclase; CH, cADPR hydrolase; ADPR, ADP-ribose; Per, phosphocreatine.
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