Search PubMed⌕ Search

Biomedical subjects

G Magnus

Publications and source records attributed to G Magnus.

10 recordsLinked to original sources
PubMed1998

Model of beta-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables.

We continue our development of a kinetic model of bursting electrical activity in the pancreatic beta-cell (J. Keizer and G. Magnus. Biophys. J. 56: 229-242, 1989), including the influence of Ca2+ handling by the mitochondria. Our minimal model of mitochondrial Ca2+ handling [G. Magnus and J. Keizer. Am. J. Physiol. 273 (Cell Physiol. 42): C717-C733, 1997] is expanded to include the D-glucose dependence of the rate of production of mitochondrial reducing equivalents. The Ca2+ dependence of the mitochondrial dehydrogenases, which is also included in the model, plays only a small role in the simulations, since the dehydrogenases appear to be maximally activated when D-glucose concentrations are sufficient to produce bursting. A previous model of ionic currents in the plasma membrane is updated using a recent experimental characterization of the dependence of the conductance of the ATP-sensitive K+ (KATP) current on adenine nucleotides. The resulting whole cell model is complex, involving 12 dynamic variables that couple Ca2+ handling in the cytoplasm and the mitochondria with electrical activity in the plasma and inner mitochondrial membranes. Simulations with the whole cell model give rise to bursting electrical activity similar to that seen in pancreatic islets and clusters of pancreatic beta-cells. The full D-glucose dose response of electrical activity is obtained if the cytosolic rate of ATP hydrolysis is a sigmoidal function of glucose. The simulations give the correct shape, period, and phase of the associated oscillations in cytosolic Ca2+, predict that the conductance of the KATP current oscillates out of phase with electrical activity [as recently observed in ob/ob mice (O. Larsson, H. Kindmark, R. Bränstrom, B. Fredholm, and P.-O. Berggren. Proc. Natl. Acad. Sci. USA 93: 5161-5165, 1996)], and make other novel predictions. In this model, bursting results because Ca2+ uptake into mitochondria during the active phase reduces the mitochondrial inner membrane potential, reducing the rate of production of ATP, which in turn activates the KATP current and repolarizes the plasma membrane.

Animals↗
PubMed1998

Model of beta-cell mitochondrial calcium handling and electrical activity. II. Mitochondrial variables.

In the preceding article [Am. J. Physiol. 274 (Cell Physiol. 43): C1158-C1173, 1998], we describe the development of a kinetic model for the interaction of mitochondrial Ca2+ handling and electrical activity in the pancreatic beta-cell. Here we describe further results of those simulations, focusing on mitochondrial variables, the rate of respiration, and fluxes of metabolic intermediates as a function of D-glucose concentration. Our simulations predict relatively smooth increases of O2 consumption, adenine nucleotide transport, oxidative phosphorylation, and ATP production by the tricarboxylic acid cycle as D-glucose concentrations are increased from basal to 20 mM. On the other hand, we find that the active fraction of pyruvate dehydrogenase saturates, due to increases in matrix Ca2+, near the onset of bursting electrical activity and that the NADH/NAD+ ratio in the mitochondria increases by roughly an order of magnitude as glucose concentrations are increased. The mitochondrial ATP/ADP ratio increases by factor of < 2 between the D-glucose threshold for bursting and continuous spiking. According to our simulations, relatively small changes in mitochondrial membrane potential (approximately 1 mV) caused by uptake of Ca2+ are sufficient to alter the cytoplasmic ATP/ADP ratio and influence ATP-sensitive K+ channels in the plasma membrane. In the simulations, these cyclic changes in the mitochondrial membrane potential are due to synchronization of futile cycle of Ca2+ from the cytoplasm through mitochondria via Ca2+ uniporters and Na+/Ca2+ exchange. Our simulations predict steady mitochondrial Ca2+ concentrations on the order of 0.1 microM at low glucose concentrations that become oscillatory with an amplitude on the order of 0.5 microM during bursting. Abrupt increases in mitochondrial Ca2+ concentration > 5 microM may occur during continuous electrical activity.

Adenosine Triphosphate↗
PubMed1997

Minimal model of beta-cell mitochondrial Ca2+ handling.

We develop a simplified, but useful, mathematical model to describe Ca2+ handling by mitochondria in the pancreatic beta-cell. The model includes the following six transport mechanisms in the inner mitochondrial membrane: proton pumping via respiration and proton uptake by way of the F1Fzero-ATPase (adapted from D. Pietrobon and S. Caplan. Biochemistry 24: 5764-5778, 1985), a proton leak, adenine nucleotide exchange, the Ca2+ uniporter, and Na+/Ca2+ exchange. Each mechanism is developed separately into a kinetic model for the rate of transport, with parameters taken from experiments on isolated mitochondrial preparations. These mechanisms are combined in a modular fashion first to describe state 4 (nonphosphorylating) and state 3 (phosphorylating) mitochondria with mitochondrial NADH and Ca2+ concentrations as fixed parameters and then to describe Ca2+ handling with variable mitochondrial Ca2+ concentration. Simulations are compared to experimental measurements and agree well with the threshold for Ca2+ uptake, measured mitochondrial Ca2+ levels, and the influence of Ca2+ on oxygen uptake. In the absence of Ca2+ activation of mitochondrial dehydrogenases, the simulations predict a significant reduction in the rate of production of ATP that involves a "short circuit" via Ca2+ uptake through the uniporter. This effect suggests a potential role for mitochondrial Ca2+ handling in determining the ATP-ADP ratio in the pancreatic beta-cell.

Animals↗
PubMed1993

Asking for more help.

Explore the source record for details and available documents.

Personnel Staffing and Scheduling↗
PubMed1989

ATP-sensitive potassium channel and bursting in the pancreatic beta cell. A theoretical study.

Based on the existence of ATP-sensitive potassium channels in the plasma membrane of pancreatic beta cells, we develop a quantitative explanation of the electrical activity observed in pancreatic islets. The proposed mechanism involves the voltage-dependent inward calcium and outward potassium currents described by Rorsman and Trube (1986), which are voltage-activated when an increase in the cytoplasmic ATP/ADP ratio decreases the conductance of the ATP-sensitive potassium channels. It is proposed that modulation of the ATP/ADP ratio occurs through calcium inhibition of oxidative phosphorylation. In this picture the mitochondria serve as a transducer of metabolic activity whose sensitivity is modulated by cytosolic calcium. Solution of the differential equations that describe this mechanism gives rise to both bursting and continuous spiking electrical activity similar to that observed experimentally. While the mechanism for bursting in this model involves the ATP/ADP ratio, the feedback is still provided by calcium, as originally proposed by Chay and Keizer (1983) using a Ca2+-activated potassium conductance. A mixed-model, which includes both ATP-sensitive and Ca2+-activated potassium conductances, also reproduces the experimentally observed electrical activity and may correspond more closely to the actual situation in vivo.

Adenosine Diphosphate↗
PubMed1985

Circadian toxicology of cyclosporin.

Cyclosporin (Cs), a cyclic nonpolar undecapeptide of fungal origin, has potent immunosuppressive and antiparasitic activities, and renal and hepatic toxicities, the mechanisms of which are not worked out. Many nephrotoxins and hepatotoxins are predictably more or less harmful, depending upon the circadian stage at which they are administered. In order to find treatment schedules that might damage the animal least, the toxicity of 20 mg kg-1 day-1 of Cs given intraperitoneally was studied at six different circadian stages in adult male Lewis rats. Cs toxicity was gauged by body temperature decline, body weight loss, and survival time. Rectal temperatures over a 24-hr span during the 2 days prior to the first death revealed that rats treated during darkness were 1.6 +/- 0.3 degree C cooler than vehicle-treated controls, whereas rats treated during the light span were only 0.4 +/- 0.2 degree C cooler than controls (p less than 0.01). Rats treated in darkness lost twice as much weight compared to those treated in light (20 +/- 2 versus 10 +/- 2%, p less than 0.01). Rats receiving daily Cs in the dark span lived an average of 28 +/- 5 days compared with 44 +/- 4 days for animals getting Cs during the light span (p less than 0.05). Three separate nonspecific measures of drug toxicity confirmed that there was substantial circadian stage dependence to Cs toxicity. The safest time for the drug in rats was 2 to 10 hr after lighting onset, a time when rats are usually beginning their diurnal rest and/or sleep span.

Animals↗