The inward rectifier K⁺ channel Kir2.1 participates in the maintenance of the cell membrane potential in a variety of cells including neurons and cardiac myocytes. Mutations of KCNJ2 encoding Kir2.1 underlie the Andersen-Tawil syndrome, a rare disorder characterized clinically by periodic paralysis, cardiac dysrhythmia and skeletal abnormalities. Maintenance of cardiac cell membrane potential is decreased in ischemia, which is known to stimulate the AMP-activated serine/threonine protein kinase (AMPK). This energy sensing kinase stimulates energy production and limits energy utilisation. The present study explored whether AMPK regulates Kir2.1. To this end, cRNA encoding Kir2.1 was injected into Xenopus oocytes with and without additional injection of wild type AMPK (AMPKa1+AMPKb1+AMPKg1), of the constitutively active ^gR70QAMPK (a1b1g1(R70Q)), of the kinase dead mutant ^aK45RAMPK (a1(K45R)b1g1), or of the ubiquitin ligase Nedd4-2. Kir2.1 activity was determined in two electrode voltage clamp experiments. Moreover, Kir2.1 abundance in the cell membrane was determined by immunostaining and subsequent confocal imaging. As a result, wild type and constitutively active AMPK significantly reduced Kir2.1-mediated currents and reduced Kir2.1 abundance in the cell membrane. In conclusion, AMPK is a potent regulator of Kir2.1.