Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to meet demand. The pulmonary arteries and carotid bodies are key systems in this respect. Hypoxic pulmonary vasoconstriction aids ventilation-perfusion matching in the lung by diverting blood flow from areas with an O2 deficit to those rich in O2, while a fall in arterial pO2 increases sensory afferent discharge from the carotid body to elicit corrective changes in breathing patterns. Considered here is the new concept that hypoxia, by inhibiting oxidative phosphorylation, activates AMP-activated protein kinase (AMPK) leading to consequent phosphorylation of target proteins such as ion channels, which mediate pulmonary artery constriction and carotid body activation. With respect to the role of AMPK in O2 sensing, investigations on pulmonary arterial smooth muscle have perhaps provided the strongest support [1]. Thus, exposure of pulmonary arterial smooth muscle to hypoxia precipitated an increase in the AMP/ATP ratio, and concomitant activation of AMPK and phosphorylation of acetyl CoA carboxylase (ACC), an established marker of AMPK action. Moreover, AMPK activation and ACC phosphorylation was induced in pulmonary arterial smooth muscle both by the mitochondrial inhibitor phenformin and by AICAR, which activates AMPK without affecting the cellular AMP:ATP ratio, and each agent induced an increase in the intracellular Ca2+ concentration by mobilizing intracellular stores in acutely isolated pulmonary arterial smooth muscle cells as does hypoxia. Most significantly, however, AMPK activation by AICAR evoked a slow, sustained and reversible constriction of pulmonary artery rings that exhibits all the primary characteristics of hypoxic pulmonary vasoconstriction, which may be blocked by the non-selective AMPK antagonist compound C. New data obtained using both AMPK activators and intracellular dialysis of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2β2γ1) now demonstrate that recombinant Kv2.1 and Kv1.5 are directly phosphorylated and modulated by AMPK, and in a manner consistent with the differential effects of both hypoxia, mitochondrial inhibitors and AMPK on Kv currents recorded in arterial smooth muscle cells of conduit and resistance sized pulmonary arteries, respectively. Consistent with a general role for AMPK in hypoxia-response coupling, we have previously shown that AMPK activation, like hypoxia, also activates the carotid body by causing depolarization of type I cells, triggering voltage-gated Ca2+ influx and consequent secretion of transmitters to excite afferent sensory neurons [2]. Furthermore, we showed that carotid body activation by hypoxia is blocked by the non-selective AMPK antagonist compound C. Our most recent investigations now provide further evidence in support of a role for AMPK. In the rat, depolarization of type I cells arises from inhibition of a TASK-like, leak K current and BKCa channels. We have now demonstrated that intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2β2γ1) inhibits recombinant TASK-3 (but not TASK-1) and BKCa channels expressed in HEK293 cells. With respect to BKCa channels parallel phosphorylation studies have confirmed that the immunoprecipitated channel protein is a direct substrate for AMPK, that channel inhibition by AMPK is splice variant specific and in a manner consistent with the BKCa splice variant expressed in type I cells. Perhaps most significantly, however, in AMPK knockout mice the ventilatory response to hypoxia is attenuated. In conclusion, AMPK may be sufficient and necessary for hypoxia-response coupling and may regulate O2 and thereby energy (ATP) supply at the whole body as well as the cellular level [3].