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

Haiping Hao ^* , Daniel E. Zak ^* , Thomas Sauter  , James Schwaber  and Babatunde A. Ogunnaike ^*

^* Department of Chemical Engineering and Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19176; Daniel Baugh Institute for Functional Genomics and Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Institute for System Dynamics and Control Engineering, University of Stuttgart, Stuttgart, Germany

Correspondence: Address reprint requests to Dr. Babatunde A. Ogunnaike, William L. Friend Professor, Dept. of Chemical Engineering, University of Delaware, Newark, DE 19176. Tel.: 302-831-4504; Fax: 302-831-1048; E-mail: ogunnaik{at}che.udel.edu.

Increasing evidence suggests an important role for VPAC₂-activated signal transduction pathways in maintaining a synchronized biological clock in the suprachiasmatic nucleus (SCN). Activation of the VPAC₂ signaling pathway induces per1 gene expression in the SCN and phase-shifts the circadian clock. Mice without the VPAC₂ receptor lack an overt, coherent circadian rhythm in clock gene expression, SCN neuron firing rate, and locomotor behavior. Using a systems approach, we have developed a kinetic model integrating VPAC₂ signaling mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and leading to induced circadian clock gene expression. We fit the model to experimental data from the literature for cAMP accumulation, PKA activation, cAMP-response element binding protein phosphorylation, and per1 induction. By linking the VPAC₂ model to a published circadian clock model, we also simulated clock phase shifts induced by vasoactive intestinal polypeptide (VIP) and matched experimental data for the VIP response. The simulated phase response curve resembled the hamster response to a related neuropeptide, GRP_1–27, and light. Simulations using pulses of VIP revealed that the system response is extraordinarily robust to input signal duration, a result with physiologically relevant consequences. Lastly, simulations using varied receptor levels matched literature experimental data from animals overexpressing VPAC₂ receptors.

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