title: The Phase Lag between Agonist-Induced Oscillatory Ca2+and IP3Signals Does Not Imply Causality (December 2015).
abstract: Activated phospholipase C (PLC*) generates 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from phosphatidyl inositol (PIP2). The DAG remains in the plasma membrane and co-activates conventional protein kinase C (PKC) with Ca2+. We have developed a mathematical model for the activation of the Ca2+-dependent PKC and its negative feedback on phospholipase C (PLC) and coupled it to the De Young-Keizer model for IP3mediated Ca2+oscillations. The model describes the cascade of reactions for the translocation of PKC to plasma membrane, and simulates activation of Ca2+and diacylglycerol (DAG) oscillations. The model demonstrates that oscillations in Ca2+and DAG are possible with or without a positive Ca2+feedback on phospholipase C consistent with experiment. In many experimental studies, the timing of the peaks of the Ca2+and IP3oscillations have been used to suggest causality, i.e. that the IP3oscillations cause the Ca2+oscillations. The model is used to explore this question. To this end, the positive and negative feedback between Ca2+and IP3production are modulated, resulting in changes to the phase lag between the peaks in [Ca2+]cytand [IP]cyt. The model simulates a possible experimental protocol that can be used to differentiate whether or not the positive feedback of Ca2+on PLC is needed for the oscillations.
authors.affiliation: Department of Pharmacology, University of California Davis, Davis CA 95616 USA.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Molecular Neuroscience Department and School of Systems Biology, George Mason University, Fairfax, VA 22030 USA.
authors.forename: M Saleet
authors.initials: MS
authors.lastname: Jafri
keywords: calcium oscillation; computational model; diacyl glycerol (DAG); phospholipase C (PLC); protein kinase C (PKC)