Modeling the VPAC2-Activated cAMP/PKA Signaling Pathway: From Receptor to Circadian Clock Gene Induction

Mice lacking the VPAC2 receptor show no coherent circadian rhythm in clock gene expression.

• Activation of the VPAC2 signaling pathway may induce per1 gene expression in the suprachiasmatic nucleus.
• Phase shifts in the circadian clock could be linked to VPAC2-mediated signaling through the cyclic AMP (cAMP)/protein kinase A (PKA) pathway.
• A kinetic model was developed to integrate VPAC2 signaling and simulate induced circadian clock gene expression.
• The simulated phase response curve for VPAC2 signaling resembled responses to vasoactive intestinal polypeptide (VIP) observed in hamsters.
• The system response to VIP input is robust against variations in signal duration, which may have physiological implications.
• Simulations matched experimental data from animals with overexpressed VPAC2 receptors.

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