InsP3R-Ca(2+) signaling takes center stage in the hormonal regulation of hepatic gluconeogenesis.
During fasting, dephosphorylation-dependent activation of the CREB coactivator CRTC2 by glucagon is crucial for activation of the hepatic gluconeogenic program, but the molecular mechanism by which hormones regulate CRTC2 activation remains unclear. A recent report in Nature showed that PKA-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor (InsP3R) induces Ca mobilization, leading to increase in the phosphatase activity of calcineurin and the subsequent dephosphorylation of CRTC2, thereby resulting in the induction of gluconeogenic gene expression. It also showed that insulin-dependent phosphorylation of InsP3R by Akt inhibits Ca mobilization and CRTC2 dephosphorylation, resulting in the suppression of gluconeogenesis.
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. mmatsumoto@ri.ncgm.go.jp
Michihiro
M
Matsumoto
D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005943:Gluconeogenesis; D022781:Hepatocytes / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
C493245:CRTC2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium