Biomedical subjects

A L Fogelson

Publications and source records attributed to A L Fogelson.

5 recordsLinked to original sources

PubMed1998

Membrane binding-site density can modulate activation thresholds in enzyme systems.

The kinetic equations are analysed for a model system which is motivated by the reactions of blood coagulation, and which involves two zymogen-enzyme pairs each of which can exist in solution phase or bound to a membrane. The enzyme of each pair activates the zymogen of the other pair, and each enzyme is subject to first-order inactivation both in solution and when bound to the membrane. If enzyme activation happens exclusively or predominantly in the membrane phase, then the system displays a threshold response which can be modulated by varying the density of membrane binding sites for the zymogens and enzymes. For low densities of membrane binding sites, the system's response when challenged by a dose of enzyme quickly decays away. For high enough densities of membrane binding sites, the system responds with substantial and sustained enzyme production. Thus variations in surface-binding site densities can serve as a "switch", drastically altering the responsiveness of the system. Such a binding-site-mediated switching mechanism could have profound importance to the regulation of enzyme systems, in particular, the blood coagulation system.

Binding Sites↗

PubMed1996

Platelet dense-granule centralization and the persistence of ADP secretion.

After activation of a human platelet, its adenosine diphosphate (ADP)-containing dense granules are moved toward the platelet's center and release their ADP into the channels of the open canalicular system (OCS). Mathematical modeling is used to investigate a possible role of this centralization in prolonging the duration of ADP secretion compared with direct release at the platelet's plasma membrane. A key parameter is the degree to which the diffusion of ADP through the narrow and tortuous channels of the OCS is slower than ADP diffusion in plasma. For small but physiologically plausible values of this parameter and with use of literature-based values for the amount and concentration of dense-granule, ADP, the platelet serves as a continuing source of ADP; the concentration of ADP in the immediate environment of the platelet remains high enough to activate nearby platelets for 5-13 s, many times longer than if ADP were released directly at the plasma membrane.

Adenosine Diphosphate↗

PubMed1993

Activation waves in a model of platelet aggregation: existence of solutions and stability of travelling fronts.

Platelets cohere to one another to form platelet aggregates as part of the blood's clotting response. The ability of a platelet to participate in this process depends on its prior 'activation' by chemicals released into the blood plasma by other activated platelets. We study the piecewise-linear system of reaction-diffusion equations which, in one spatial dimension, describe the chemically-mediated spread of platelet activation. We establish the existence of classical solutions to this system of equations, and show that these solutions do not blow up in finite time. We also explicitly construct travelling front solutions and discuss their stability. Finally, we present numerical evidence which suggests that for a broad range of initial data with the correct limiting values at +/- infinity, the solution to the initial value problem rapidly evolves into the travelling front solution provided the front is linearly stable.

Animals↗

PubMed1986

Relationship between transmitter release and presynaptic calcium influx when calcium enters through discrete channels.

We have used a three-dimensional diffusion model of calcium entering the presynaptic nerve terminal through discrete channels to simulate experiments relating transmitter release to presynaptic calcium current. The relationship will be less than linear, or will curve downward, if calcium channels are well separated. It will resemble a power-law function with exponent less than the cooperativity of calcium action if channels are clustered closer together. Large presynaptic depolarizations elicit more release than small depolarizations admitting the same calcium influx. This occurs because large pulses open more channels near each other, with the result that the calcium concentration near release sites is greater, due to overlap of calcium diffusing from adjacent channels.

Calcium↗

PubMed1985

Presynaptic calcium diffusion from various arrays of single channels. Implications for transmitter release and synaptic facilitation.

A one-dimensional model of presynaptic calcium diffusion away from the membrane, with cytoplasmic binding, extrusion by a surface pump, and influx during action potentials, can account for the rapid decay of phasic transmitter release and the slower decay of synaptic facilitation following one spike, as well as the very slow decline in total free calcium observed experimentally. However, simulations using this model, and alternative versions in which calcium uptake into organelles and saturable binding are included, fail to preserve phasic transmitter release to spikes in a long tetanus. A three-dimensional diffusion model was developed, in which calcium enters through discrete membrane channels and acts to release transmitter within 50 nm of entry points. Analytic solutions of the equations of this model, in which calcium channels were distributed in active zone patches based on ultrastructural observations, were successful in predicting synaptic facilitation, phasic release to tetanic spikes, and the accumulation of total free calcium. The effects of varying calcium buffering, pump rate, and channel number and distribution were explored. Versions appropriate to squid giant synapses and frog neuromuscular junctions were simulated. Limitations of key assumptions, particularly rapid nonsaturable binding, are discussed.

Action Potentials↗