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. 2004 Oct 15;383(Pt 2):353-60.
doi: 10.1042/BJ20040629.

Dual sensitivity of sarcoplasmic/endoplasmic Ca2+-ATPase to cytosolic and endoplasmic reticulum Ca2+ as a mechanism of modulating cytosolic Ca2+ oscillations

Kojiro Yano  1 , Ole H Petersen, Alexei V Tepikin
Affiliations

Dual sensitivity of sarcoplasmic/endoplasmic Ca2+-ATPase to cytosolic and endoplasmic reticulum Ca2+ as a mechanism of modulating cytosolic Ca2+ oscillations

Kojiro Yano et al. Biochem J. .

Abstract

The effects of ER (endoplasmic reticulum) Ca2+ on cytosolic Ca2+ oscillations in pancreatic acinar cells were investigated using mathematical models of the Ca2+ oscillations. We first examined the mathematical model of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) to reproduce the highly co-operative inhibitory effect of Ca2+ in the ER lumen on ER Ca2+ uptake in the acinar cells. The model predicts that luminal Ca2+ would most probably inhibit the conversion of the conformation state with luminal Ca2+-binding sites (E2) into the conformation state with cytoplasmic Ca2+-binding sites (E1). The SERCA model derived from this prediction showed dose-response relationships to cytosolic and luminal Ca2+ concentrations that were consistent with the experimental data from the acinar cells. According to a mathematical model of cytosolic Ca2+ oscillations based on the modified SERCA model, a small decrease in the concentration of endoplasmic reticulum Ca2+ (approx. 20% of the total) was sufficient to abolish the oscillations. When a single type of IP3R (IP3 receptor) was included in the model, store depletion decreased the spike frequency. However, the frequency became less sensitive to store depletion when we added another type of IP3R with higher sensitivity to the concentration of free Ca2+ in the cytosol. Bifurcation analysis of the mathematical model showed that the loss of Ca2+ from the ER lumen decreased the sensitivity of cytosolic Ca2+ oscillations to IP3 [Ins(1,4,5)P3]. The addition of a high-affinity IP3R did not alter this property, but significantly decreased the sensitivity of the spike frequency to IP3. Our mathematical model demonstrates how luminal Ca2+, through its effect on Ca2+ uptake, can control cytosolic Ca2+ oscillations.

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Figures

Figure 1
Figure 1. Reaction cycle and dose–response of turnover rate to cytosolic and luminal Ca2+ in SERCA2b model
(A) Reaction cycle of SERCA. Clockwise direction of a reaction in the cycle is defined as a ‘forward’ reaction. The numbers shown with the reactions are used in the text in order to refer to individual reactions. (B1) Estimated dose–response of the turnover rate of SERCA2b against [Ca2+]c and [Ca2+]ER. Note that [Ca2+]c is expressed on a logarithmic scale and [Ca2+]ER is on a linear scale (this representation is chosen for visual convenience). (B2) Turnover rate at different [Ca2+]ER when [Ca2+]c=1 μM. (B3) Turnover rate at different [Ca2+]c when [Ca2+]ER=10 μM.
Figure 2
Figure 2. Simulation of cytosolic Ca2+ oscillations in a pancreatic acinar cell during gradual store depletion
The gradual depletion of the Ca2+ store in the model was achieved by the extrusion of cytosolic Ca2+ by PMCA and the lack of compensating Ca2+ influx through the plasma membrane. (A) [Ca2+]c (lower trace) and [Ca2+]ER (upper trace) during the simulation. At the resting condition [Ca2+]c=0.08 μM and [Ca2+]ER=200 μM. The cell was stimulated by increasing [IP3] from 0 to 0.254 μM. (B) The rise time (•) and the decay time (○) of cytosolic Ca2+ spikes during the simulation.
Figure 3
Figure 3. Bifurcation analysis of the modifications of Ca2+ oscillations by store depletion
(A) A typical bifurcation diagram of [Ca2+]c against [IP3] in IP3-induced Ca2+ oscillations is presented. Steady-state solutions (solid line) and the maxima and the minima of [Ca2+]c during Ca2+ oscillations (broken line) are shown. [Ca2+]c will be stationary when [IP3] is outside the ‘oscillatory’ area (1). [Ca2+]c oscillates when [IP3] is in the ‘oscillatory’ area, which is encompassed by the broken line (2 and 3). Oscillation frequency is faster at higher [IP3] (3) than lower [IP3] (2). (B) Bifurcation diagrams of [Ca2+]c against [IP3] in the whole-cell model. Steady-state solutions (solid line), the maxima and the minima of [Ca2+]c during Ca2+ oscillations (broken line) are shown. S=200 μM in control and S=160 μM in depleted store.
Figure 4
Figure 4. Simulation of cytosolic Ca2+ oscillations in a pancreatic acinar cell during gradual store depletion when two subtypes of IP3R are present
The store was depleted gradually in the same way as in Figure 2. (A) [Ca2+]c (lower trace) and [Ca2+]ER (upper trace) in the whole-cell model with two subtypes of IP3R. In this simulation, it was assumed that the ‘high-affinity’ IP3R subtype had three times higher affinity to cytosolic Ca2+ than the subtype used for the simulation in Figure 2. (B) The rise time (•) and the decay time (○) of Ca2+ spikes during the simulation. (C) Bifurcation diagrams of [Ca2+]c against [IP3] in the whole-cell model. Steady-state solutions (solid line), the maxima and the minima of periodic orbits (broken line) are shown. S=200 μM in control and S=160 μM in depleted store.
Figure 5
Figure 5. Relationship between [IP3] and oscillation periods when one or two IP3R subtypes were present
The traces compare the relationship between the period of cytosolic Ca2+ oscillations and [IP3] in the mathematical models with one and two subtypes of IP3R.
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