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

Paulo F.V. Bizerra, Eduardo H. Gilglioni, Hang Lam Li, Simei Go, Ronald P.J. Oude Elferink, Arthur J. Verhoeven, Jung Chin Chang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 in HepG2 cells to study glycogen breakdown in real time, we showed that cAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells and the downstream cAMP effectors. While the canonical tmAC-cAMP-PKA signaling promotes glycogenolysis, we demonstrate here that the non-canonical sAC-cAMP-Epac1 signaling suppresses glycogenolysis. Mechanistically, suppression of sAC-cAMP-Epac1 leads to Ser-15 phosphorylation and thereby activation of the liver-form glycogen phosphorylase to promote glycogenolysis. Our findings highlight the importance of cAMP microdomain organization for distinct metabolic regulation and establish sAC as a novel regulator of glycogen metabolism.

Original languageEnglish
Article number119585
Number of pages17
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number1
Publication statusPublished - Jan 2024


  • cAMP signaling microdomains
  • Cyclic AMP
  • Exchange protein directly activated by cAMP (Epac)
  • Glycogen breakdown
  • Glycogenolysis
  • Soluble adenylyl cyclase


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