BIOPHYSICAL THEORY AND MODELING |
Modeling the VPAC2 activated cAMP/PKA signaling pathway: From receptor to circadian clock gene induction
Haiping Hao 1, Daniel E. Zak 2, Thomas Sauter 3, James Schwaber 1 and Babatunde A. Ogunnaike 2*
1 Thomas Jefferson University
2 University of Delaware
3 University of Stuttgart
* To whom correspondence should be addressed. E-mail: ogunnaik{at}che.udel.edu.
Submitted on April 26, 2005
Revised on June 12, 2005
Accepted on 21 November 2005
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Abstract |
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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 cAMP/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, CREB phosphorylation, and per1 induction. By linking the VPAC2 model to a published circadian clock model, we also simulated clock phase shifts induced by VIP and matched experimental data for the VIP response. The simulated phase response curve resembled the hamster response to a related neuropeptide, GRP1-27, 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 over-expressing VPAC2 receptors.
Key Words:
Ordinary differential equations, cell signaling, per1, phase-shifting, suprachiasmatic nucleus, vasoactive intestinal polypeptide
