Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane

Summary Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1∼ADCY9 ) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10 ). By employing high-resolution extracellular flux analysis to study glycogen breakdown in real time, we show here thatcAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we demonstrate that the non-canonical sAC-cAMP-Epac1 signalling suppresses glycogenolysis in a variety of cell types. Our findings demonstrate the importance of cAMP microdomain organization in glycogen metabolism and reveal a novel role of sAC in energy metabolism during glucose deprivation.