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Insights into Delivery of Somatic Calcium Signals to the Nucleus During LTP Revealed by Computational Modeling

Ximing, LI
http://orcid.org/0000-0002-5157-697X
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou152236301476345

Abstract Details

2018, Doctor of Philosophy (PhD), Ohio University, Biological Sciences (Arts and Sciences).
Calcium (Ca2+) signals are essential for neurons. They are involved in a variety of cell activities including long-term potentiation (LTP), our best model for the molecular basis of learning and memory. How Ca2+ signals reach the nucleus to activate genes during LTP has been debated for decades. One set of ideas, namely the "nuclear Ca2+ hypothesis" states that Ca2+ ions entering the neuron at the synapse or soma can diffuse across the cytoplasm to enter the nucleus. In contrast, another line of studies emphasizes the role of local Ca2+ signals at the soma and states that carriers are required to deliver the local Ca2+ into the nucleus via an excitation-transcription coupling mechanism (E-T coupling). In this study, I use a computational modeling approach to investigate these two mechanisms. In particular, I examine under what conditions it is possible for local Ca2+ signals to reach the nucleus through carrier-mediated diffusion. The proposed mechanisms involve Ca2+, calmodulin (CaM), and Ca2+-CaM-dependent protein kinase II (CaMKII). The Ca2+-CaM-CaMKII reaction network has been studied for many years in both experiments and computational models. However, due to the complexity of CaMKII, few models have included sufficient details in how CaMKII as a multi-subunit complex interacts with Ca2+-CaM. A major problem is the combinatorial explosion in the number of states that must be simulated. I have adapted an existing stochastic particle-based reaction-diffusion simulator, Smoldyn, to manage the problem of combinatorial explosion. With this new method, spatial and temporal aspects of the signaling network can be studied without compromising biochemical details. Using a physiologically realistic Ca2+ input, I use this new method to examine the characteristics of the Ca2+-CaM-CaMKII network, in particular, the response to the frequency of Ca2+ influx. I also develop a novel approach to analyze the behavior of the network by counting reaction occurrences. This approach intuitively predicts a "preferred pathway" whereby certain CaM states are more often traversed than others when a particular Ca2+ input is given or when a specific amount CaM is present. CaM availability and Ca2+ diffusion rate can affect the frequency dependence of CaMKII activation, change the "preferred pathway", and affect CaMKII phosphorylation. I subsequently examined the effects of neurogranin (Ng), a widely existing CaM binding protein in neurons, on the Ca2+-CaM-CaMKII network. Ng holds a CaM pool at the cell resting state. Upon Ca2+ influx, CaM molecules are gradually released. The size of the pool, i.e., the amount of the "extra CaM", can positively affect CaMKII phosphorylation, but only up to an upper bound. Similarly, even when Ng is not present, increasing the CaM amount adds to CaMKII phosphorylation but only to an upper bound. Finally, I integrate the Ca2+-CaM-CaMKII network into a three-compartment model to test the nuclear Ca2+ hypothesis and the E-T coupling mechanism. I examine under what conditions Ca2+ signals from the surface membrane can reach the nucleus in the presence of endogenous Ca2+ buffers such as Calbindin. I find that when Ca2+ ions diffuse fast, they can reach the nucleus quickly without the need of CaM and CaMKII. Only when Ca2+ diffusion is considerably reduced and CaM diffusion is moderately slowed, can CaMKII improve the delivery of Ca2+-CaM to the nucleus. This result suggests that for effective E-T coupling to occur, diffusion barriers should be present around L-type channels to significantly slow Ca2+ diffusion.
William Holmes (Advisor)
182 p.
Neurosciences
stochastic reaction-diffusion models; calcium signaling; calmodulin; CaMKII

Recommended Citations

Citations

  • Ximing, L. (2018). Insights into Delivery of Somatic Calcium Signals to the Nucleus During LTP Revealed by Computational Modeling [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou152236301476345

    APA Style (7th edition)

  • Ximing, LI. Insights into Delivery of Somatic Calcium Signals to the Nucleus During LTP Revealed by Computational Modeling. 2018. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou152236301476345.

    MLA Style (8th edition)

  • Ximing, LI. "Insights into Delivery of Somatic Calcium Signals to the Nucleus During LTP Revealed by Computational Modeling." Doctoral dissertation, Ohio University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou152236301476345

    Chicago Manual of Style (17th edition)

ohiou152236301476345
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This open access ETD is published by Ohio University and OhioLINK.