RGD Reference Report - Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. - Rat Genome Database

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Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.

Authors: Wang, Yiguo  Li, Gang  Goode, Jason  Paz, Jose C  Ouyang, Kunfu  Screaton, Robert  Fischer, Wolfgang H  Chen, Ju  Tabas, Ira  Montminy, Marc 
Citation: Wang Y, etal., Nature. 2012 Apr 8;485(7396):128-32. doi: 10.1038/nature10988.
RGD ID: 13432287
Pubmed: PMID:22495310   (View Abstract at PubMed)
PMCID: PMC3343222   (View Article at PubMed Central)
DOI: DOI:10.1038/nature10988   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q3U18213432287PMID:22495310IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Itpr1  (inositol 1,4,5-trisphosphate receptor, type 1)


Additional Information