Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells

Pedersen, Morten Gram; Salunkhe, Vishal A.; Svedin, Emma; Edlund, Anna; Eliasson, Lena

doi:10.1371/journal.pone.0103874

Cited by 4 publications

(3 citation statements)

References 63 publications

(110 reference statements)

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“…We also study the relationship between Ca 2+ influx and exocytosis. The results of the devised exocytosis model confirm that the granule secretion is generally linearly related to the integral of Ca 2+ current, as experimentally observed [25–29] and theoretically justified [24]. Surprisingly, for the case of inactivating CaVs, our analysis shows a change of the linear relation between p Y and Q Ca due to near-complete inactivation of CaVs.…”

Section: Discussionsupporting

confidence: 86%

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

Montefusco

Pedersen

2018

Computational and Mathematical Methods in Medicine

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Hormones and neurotransmitters are released from cells by calcium-regulated exocytosis, and local coupling between Ca2+ channels (CaVs) and secretory granules is a key factor determining the exocytosis rate. Here, we devise a methodology based on Markov chain models that allows us to obtain analytic results for the expected rate. First, we analyze the property of the secretory complex obtained by coupling a single granule with one CaV. Then, we extend our results to a more general case where the granule is coupled with n CaVs. We investigate how the exocytosis rate is affected by varying the location of granules and CaVs. Moreover, we assume that the single granule can form complexes with inactivating or non-inactivating CaVs. We find that increasing the number of CaVs coupled with the granule determines a much higher rise of the exocytosis rate that, in case of inactivating CaVs, is more pronounced when the granule is close to CaVs, while, surprisingly, in case of non-inactivating CaVs, the highest relative increase in rate is obtained when the granule is far from the CaVs. Finally, we exploit the devised model to investigate the relation between exocytosis and calcium influx. We find that the quantities are typically linearly related, as observed experimentally. For the case of inactivating CaVs, our simulations show a change of the linear relation due to near-complete inactivation of CaVs.

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Section: Discussionsupporting

confidence: 86%

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

Montefusco

Pedersen

2018

Computational and Mathematical Methods in Medicine

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“…However there was a large overlap between the two distributions, suggesting that exocytosis also occurs at some distance from Ca 2+ channels and not only from microdomains. Using electrophysiological techniques, we reached a similar conclusion in another study [59]. This also corresponds to the conclusions in the modeling study by Klingauf & Neher [54].…”

Section: Mathematical and Statistical Modeling Of Local Casupporting

confidence: 90%

“…We have applied the theory from the previous section to data from pancreatic α-cells [79] and β-cells [13,59] to investigate whether previous interpretations of depolarization-evoked exocytosis are supported when Ca 2+ current inactivation is taken into account. We applied linear mixed-effects modeling to handle cell-to-cell heterogeneity and the fact that data was obtained by applying depolarizations of different lengths to each cell, creating clustered data (Section 2.3).…”

Section: Mixed-effects Modeling Of Pulse-length Capacitance Datamentioning

confidence: 99%

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

Pedersen

Tagliavini

Cortese

et al. 2017

Mathematical Biosciences

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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.

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Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting β-cells by cAMP-regulated transcriptional co-activator 1 and salt-inducible kinases

Malm

Mollet

Berggreen

et al. 2016

Molecular and Cellular Endocrinology

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Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells

Cited by 4 publications

References 63 publications

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

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

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

Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting β-cells by cAMP-regulated transcriptional co-activator 1 and salt-inducible kinases

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Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells

Cited by 4 publications

References 63 publications

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

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

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

Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting β-cells by cAMP-regulated transcriptional co-activator 1 and salt-inducible kinases

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

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