TY - JOUR
T1 - Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane
AU - Bizerra, Paulo F. V.
AU - Gilglioni, Eduardo H.
AU - Li, Hang Lam
AU - Go, Simei
AU - Oude Elferink, Ronald P. J.
AU - Verhoeven, Arthur J.
AU - Chang, Jung-Chin
N1 - Publisher Copyright: © 2023 The Authors
PY - 2024/1/1
Y1 - 2024/1/1
N2 - 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.
AB - 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.
KW - Cyclic AMP
KW - Exchange protein directly activated by cAMP (Epac)
KW - Glycogen breakdown
KW - Glycogenolysis
KW - Soluble adenylyl cyclase
KW - cAMP signaling microdomains
UR - http://www.scopus.com/inward/record.url?scp=85171691893&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbamcr.2023.119585
DO - https://doi.org/10.1016/j.bbamcr.2023.119585
M3 - Article
C2 - 37714306
SN - 0167-4889
VL - 1871
JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
IS - 1
M1 - 119585
ER -