Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells

Abstract

Most endocrine cells secrete hormones as a result of Ca-regulated exocytosis, i.e., fusion of the membranes of hormone-containing secretory granules with the cell membrane, which allows the hormone molecules to escape to the extracellular space. As in neurons, electrical activity and cell depolarization open voltage-sensitive Ca channels, and the resulting Ca influx elevate the intracellular Ca concentration, which in turn causes exocytosis. Whereas the main molecular components involved in exocytosis are increasingly well understood, quantitative understanding of the dynamical aspects of exocytosis is still lacking. Due to the nontrivial spatiotemporal Ca dynamics, which depends on the particular pattern of electrical activity as well as Ca channel kinetics, exocytosis is dependent on the spatial arrangement of Ca channels and secretory granules. For example, the creation of local Ca microdomains, where the Ca concentration reaches tens of µM, are believed to be important for triggering exocytosis. Spatiotemporal simulations of buffered Ca diffusion have provided important insight into the interplay between electrical activity, Ca channel kinetics, and the location of granules and Ca channels. By confronting simulations with statistical time-to-event (or survival) regression analysis of single granule exocytosis monitored with TIRF microscopy, a direct connection between location and rate of exocytosis can be obtained at the local, single-granule level. To get insight into whole-cell secretion, simplifications of the full spatiotemporal dynamics have shown to be highly helpful. Here, we provide an overview of recent approaches and results for quantitative analysis of Ca regulated exocytosis of hormone-containing granules.

A Neuron-Glial Model of Exosomal Release in the Onset and Progression of Alzheimer's Disease

“…The experimental evidence reveals that Ca 2+ -mediated exocytosis by neurons is regulated by intracellular Ca 2+ , where electrical activity pattern determines the exocytosis Ca 2+ threshold (Pedersen et al, 2017). Electrical activity is triggered by neuron depolarization, which entails the activation of VGCCs, resulting in increased intracellular Ca 2+ concentration levels, which interfere with the mobilization of multivesicular bodies, resulting in the release of exosomes and evoking exocytosis (Shaheen et al, 2021).…”

Explicit Theoretical Analysis of How the Rate of Exocytosis Depends on Local Control by Ca2+ Channels

“…We assume a single granule, adjacent to the plasma membrane and primed for exocytosis, that can be in one of four different states depending on the number of Ca 2+ ions bound to the Ca 2+ sensor on the granule, likely synaptotagmin [14]: in G 0 with no bound Ca 2+ ions, or in G 1 with one, or in G 2 with two, or in G 3 with three bound ions. Once it is in G 3 , the granule can fuse with the membrane and release its hormone content, assuming the final state Y [6, 15]. Therefore, we use a five-state Markov chain model for describing exocytosis as shown in Figure 1(b), where the model takes values in the state space S ={ G 0 , G 1 , G 2 , G 3 , Y }, and its transition rate or generator matrix M G is given byMG=−3kCa3kCa000k−−2kCa−k−2kCa0002k−−kCa−2k−kCa0003k−−u−3k−u00000,wherek…”

“…SNARE complexes interact with other proteins, notably, Ca 2+ -sensing proteins such as synaptotagmins, which trigger exocytosis upon Ca 2+ binding. Therefore, the local Ca 2+ concentration at the Ca 2+ sensor of the exocytotic machinery is a key factor determining the probability rate of exocytosis of the secretory granule [6].…”

Modeling of Modulated Exosome Release From Differentiated Induced Neural Stem Cells for Targeted Drug Delivery

“…The experimental evidence reveals that exocytosis is regulated by intracellular calcium signaling in many different cell types [39], [40]. Neuron depolarization triggers electrical activity that involves voltage-gated Ca 2+ channels.…”