Modeling the VPAC2-activated cAMP/PKA signaling pathway: from receptor to circadian clock gene induction.
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, 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 overexpressing VPAC2 receptors.
Hao
Haiping
H
Department of Chemical Engineering and Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19176, USA.
Zak
Daniel E
DE
Sauter
Thomas
T
Schwaber
James
J
Ogunnaike
Babatunde A
BA
D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D003198:Computer Simulation; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009687:Nuclear Proteins / Q000378:metabolism; D056950:Period Circadian Proteins; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology*; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases