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This Article Full Text Full Text (PDF) All Versions of this Article: 94/3/1912    most recent 00256.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Shahrezaei, V. Articles by Delaney, K. R. Search for Related Content PubMed PubMed Citation Articles by Shahrezaei, V. Articles by Delaney, K. R.

Brevity of the Ca²⁺ Microdomain and Active Zone Geometry Prevent Ca²⁺-Sensor Saturation for Neurotransmitter Release

¹Departments of Physics, Simon Fraser University, Burnaby and ²Department of Biology, University of Victoria, Victoria, British Columbia, Canada

Submitted 10 March 2005; accepted in final form 4 May 2005

The brief time course of the calcium (Ca²⁺) channel opening combined with the molecular-level colocalization of Ca²⁺ channels and synaptic vesicles in presynaptic terminals predict sub-millisecond calcium concentration ([Ca²⁺]) transients of 100 µM in the immediate vicinity of the vesicle. This [Ca²⁺] is much higher than some of the recent estimates for the equilibrium dissociation constant of the Ca²⁺ sensor(s) that control neurotransmitter release, suggesting release should be close to saturation, yet it is well known that release is highly sensitive to changes in Ca²⁺ influx. We show that due to the brevity of the Ca²⁺ influx the binding kinetics of the Ca²⁺ sensor rather than its equilibrium affinity determine receptor occupancy. For physiologically relevant Ca²⁺ currents and forward Ca²⁺ binding rates, the effective affinity of the Ca²⁺ sensor can be several-fold lower than the equilibrium affinity. Using simple models, we show redundant copies of the binding sites increase effective affinity of the Ca²⁺ sensor for release. Our results predict that different levels of expression of Ca²⁺ binding sites could account for apparent differences in Ca²⁺ sensor affinities between synapses. Using Monte Carlo simulations of Ca²⁺ dynamics with nanometer resolution, we demonstrate that these kinetic constraints combined with vesicles acting as diffusion barriers can prevent saturation of the Ca²⁺-sensor(s) for neurotransmitter release. We further show the random positioning of the Ca²⁺-sensor molecules around the vesicle can result in the emergence of two distinct populations of the vesicles with low and high release probability. These considerations allow experimental evidence for the Ca²⁺ channel-vesicle colocalization to be reconciled with a high equilibrium affinity for the Ca²⁺ sensor of the release machinery.

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