title: Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.
abstract: In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2 (ref. 1). Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2 (refs 2, 3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs), which associate with CRTC2. After their activation, InsP(3)Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signalling reduced CRTC2 activity via the AKT-mediated inactivation of InsP(3)Rs. InsP(3)R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP(3)Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP(3)R modulate hepatic glucose production under fasting conditions and in diabetes.
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jason
authors.initials: J
authors.lastname: Goode
authors.forename: Jose C
authors.initials: JC
authors.lastname: Paz
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Robert
authors.initials: R
authors.lastname: Screaton
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Fischer
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology; D005943:Gluconeogenesis / Q000235:genetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D001786:Blood Glucose; C504923:Crtc2 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D005934:Glucagon; D000242:Cyclic AMP; D019703:Calcineurin; D002118:Calcium