Monte Carlo evaluation of quantal analysis in the light of Ca²⁺ dynamics and the geometry of secretion

Abstract.

Using the Monte Carlo technique, Ca²⁺ dynamics were simulated in the absence and presence of vesicles to gain better insight into what governs quantal release. A vesicle, represented as a flat, infinitely thin surface, was positioned parallel to the plasma membrane at a chosen distance from the locus of Ca²⁺ entry. Because vesicles act as important diffusion barriers after the synchronous opening of Ca²⁺ channels (as occurs during evoked release), [Ca²⁺] close to the plasma membrane reaches higher levels than it would in the absence of vesicles. The rise in [Ca²⁺] is greater under larger vesicles close to the plasma membrane, which thus have a higher probability of release. The power–law relationship between the [Ca²⁺] and the probability of release, and the cubic relationship between the vesicular diameter and its volume can make this relationship very steep. In contrast, when release occurs owing to fluctuations of [Ca²⁺] – as a result of Ca²⁺ release from an internal store or asynchronous opening of Ca²⁺ channels (during spontaneous release) – the effect of vesicles as diffusion barriers is less pronounced and vesicles of different sizes should have a similar probability of release. Since the preferential release of large vesicles depends on how the Ca²⁺ needed for secretion is raised (synchronously versus asynchronously), the quantal size of evoked and spontaneous release should differ. The main factors influencing the preferential release of large vesicles are the distance between vesicles and the plasma membrane, the concentration of Ca²⁺ buffers, and single-channel Ca²⁺ flux. Vesicles also have a pronounced effect on Ca²⁺ binding to buffers and on the spatio-temporal distribution of bound buffers. The greater the vesicular size and the closer their position to the plasma membrane, the more fixed buffers will be bound near the plasma membrane because of limited diffusion of Ca²⁺. Since bound fixed buffers act as "memory elements", such a change in their spatial distribution will further enhance the probability of release of large vesicles during stimulation.