Figure 3. A signalling complex assembled around IP₃Rs controls gluconeogenesis .

Glucagon and insulin exert opposing effects on hepatic gluconeogenesis. Their signalling pathways converge to a protein complex assembled around IP₃Rs, the activity of which controls phosphorylation of the transcription factor CRTC2. Dephosphorylated CRTC2 translocates to the nucleus, where it associates with CREB and stimulates transcription of genes required for gluconeogenesis. SIK2 phosphorylates CRTC2, while calcineurin dephosphorylates it. Glucagon, via a GPCR, stimulates both PLC and AC. The IP₃ produced by PLC stimulates IP₃Rs. The cAMP generated by AC stimulates PKA and that promotes dephosphorylation of CRTC2 by phosphorylating both SIK2 (inhibiting its activity) and IP₃Rs, sensitizing the latter to IP₃. The larger Ca²⁺ signal then activates calcineurin. Insulin causes activation of AKT1, which phosphorylates IP₃Rs and inhibits their activity; it thereby opposes the effects of glucagon and attenuates calcineurin activity. Phosphorylation is indicated by red circles, black arrows denote stimulation and the red arrow denotes inhibition. Abbreviations and further details in the text and tables.