Filtering of Calcium Transients by the Endoplasmic Reticulum in Pancreatic β-Cells

Department of Mathematics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
Biophysical Journal (Impact Factor: 3.97). 01/2005; 87(6):3775-85. DOI: 10.1529/biophysj.104.050955
Source: PubMed


Calcium handling in pancreatic beta-cells is important for intracellular signaling, the control of electrical activity, and insulin secretion. The endoplasmic reticulum (ER) is a key organelle involved in the storage and release of intracellular Ca2+. Using mathematical modeling, we analyze the filtering properties of the ER and clarify the dual role that it plays as both a Ca2+ source and a Ca2+ sink. We demonstrate that recent time-dependent data on the free Ca2+ concentration in pancreatic islets and beta-cell clusters can be explained with a model that uses a passive ER that takes up Ca2+ when the cell is depolarized and the cytosolic Ca2+ concentration is elevated, and releases Ca2+ when the cell is repolarized and the cytosolic Ca2+ is at a lower concentration. We find that Ca2+-induced Ca2+ release is not necessary to explain the data, and indeed the model is inconsistent with the data if Ca2+-induced Ca2+ release is a dominating factor. Finally, we show that a three-compartment model that includes a subspace compartment between the ER and the plasma membrane provides the best agreement with the experimental Ca2+ data.

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    • "The filling state of the ER modulates a store-operated current (SOC) in β-cells (42,43), the function of which is to replenish the ER with Ca2+. Changes in SOC amplitude control β-cell electrical activity (44). The amplitude of the rapid [Ca2+]ER oscillations (frequency 2–3/min) is probably too small to significantly affect SOC. "
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    ABSTRACT: Sarco-endoplasmic reticulum Ca(2+)-ATPase 2b (SERCA2b) and SERCA3 pump Ca(2+) in the endoplasmic reticulum (ER) of pancreatic β-cells. We studied their role in the control of the free ER Ca(2+) concentration ([Ca(2+)](ER)) and the role of SERCA3 in the control of insulin secretion and ER stress. β-Cell [Ca(2+)](ER) of SERCA3(+/+) and SERCA3(-/-) mice was monitored with an adenovirus encoding the low Ca(2+)-affinity sensor D4 addressed to the ER (D4ER) under the control of the insulin promoter. Free cytosolic Ca(2+) concentration ([Ca(2+)](c)) and [Ca(2+)](ER) were simultaneously recorded. Insulin secretion and mRNA levels of ER stress genes were studied. Glucose elicited synchronized [Ca(2+)](ER) and [Ca(2+)](c) oscillations. [Ca(2+)](ER) oscillations were smaller in SERCA3(-/-) than in SERCA3(+/+) β-cells. Stimulating cell metabolism with various [glucose] in the presence of diazoxide induced a similar dose-dependent [Ca(2+)](ER) rise in SERCA3(+/+) and SERCA3(-/-) β-cells. In a Ca(2+)-free medium, glucose moderately raised [Ca(2+)](ER) from a highly buffered cytosolic Ca(2+) pool. Increasing [Ca(2+)](c) with high [K] elicited a [Ca(2+)](ER) rise that was larger but more transient in SERCA3(+/+) than SERCA3(-/-) β-cells because of the activation of a Ca(2+) release from the ER in SERCA3(+/+) β-cells. Glucose-induced insulin release was larger in SERCA3(-/-) than SERCA3(+/+) islets. SERCA3 ablation did not induce ER stress. [Ca(2+)](c) and [Ca(2+)](ER) oscillate in phase in response to glucose. Upon [Ca(2+)](c) increase, Ca(2+) is taken up by SERCA2b and SERCA3. Strong Ca(2+) influx triggers a Ca(2+) release from the ER that depends on SERCA3. SERCA3 deficiency neither impairs Ca(2+) uptake by the ER upon cell metabolism acceleration and insulin release nor induces ER stress.
    Full-text · Article · Sep 2011 · Diabetes
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    • "Details of the equations are provided in the appendix. The K(ATP) current has been added to the V equation, and the Ca equation now has terms for exchange with the endoplasmic reticulum, which impart a slow component to Ca that is transmitted to I K(Ca) [6] [7]. The ADP equation models the production of ATP from ADP in the mitochondria, which is inhibited with a slow time constant by Ca 2+ via shunting of the mitochondrial membrane potential [18]. "
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    ABSTRACT: We describe an extended fast-slow analysis for the dual oscillator model (DOM) for bursting oscillations in pancreatic beta-cells, which occur on a wide range of time scales, from seconds to minutes. This wide dynamic range has been suggested to result from the interactions of a very slow metabolic, possibly glycolytic, oscillator and a faster electrical oscillator, itself containing several negative feedback mechanisms with a range of time scales. Although the high dimensionality of the slow subsystem would defeat a straightforward fast-slow analysis, we show that an approximate geometrical analysis that exploits particular features of the DOM and is based on superimposing the bifurcation diagrams of the component oscillators leads to new insights into the functioning of the system.
    Full-text · Article · Jan 2009 · SIAM Journal on Applied Dynamical Systems
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    • "As a first step in understanding the differential effects of the two SERCA knockouts, we focus on the Ca 2+ subsystem. To bypass the dynamics of the electrical subsystem, a voltage clamp protocol is used that captures the pacemaker dynamics of fast bursting (Bertram and Sherman, 2004b). In this protocol, the voltage is originally clamped at −70 mV. "
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    ABSTRACT: Cytosolic Ca2+ dynamics are important in the regulation of insulin secretion from the pancreatic beta-cells within islets of Langerhans. These dynamics are sculpted by the endoplasmic reticulum (ER), which takes up Ca2+ when cytosolic levels are high and releases it when cytosolic levels are low. Calcium uptake into the ER is through sarcoendoplasmic reticulum Ca2+-ATPases, or SERCA pumps. Two SERCA isoforms are expressed in the beta-cell: the high Ca2+ affinity SERCA2b pump and the low affinity SERCA3 pump. Recent experiments with islets from SERCA3 knockout mice have shown that the cytosolic Ca2+ oscillations from the knockout islets are characteristically different from those of wild type islets. While the wild type islets often exhibit compound Ca2+ oscillations, composed of fast oscillations superimposed on much slower oscillations, the knockout islets rarely exhibit compound oscillations, but produce slow (single component) oscillations instead. Using mathematical modeling, we provide an explanation for this difference. We also investigate the effect that SERCA2b inhibition has on the model beta-cell. Unlike SERCA3 inhibition, we demonstrate that SERCA2b inhibition has no long-term effect on cytosolic Ca2+ oscillations unless a store-operated current is activated.
    Preview · Article · Aug 2008 · Bulletin of Mathematical Biology
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