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The control of release probability at nerve terminals

Nature Reviews Neuroscience volume 20, pages 177–186 (2019)Cite this article

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Abstract

Exocytosis is a fundamental membrane fusion process by which the soluble or membrane-associated cargoes of a secretory vesicle are delivered to the extracellular milieu or the cell surface. While essential for all organs, the brain relies on a specialized form of exocytosis to mediate information flow throughout its vast circuitry. Neurotransmitter-laden synaptic vesicles fuse with the plasma membrane on cue with astonishing speed in a probabilistic process that is both tightly regulated and capable of a fascinating array of plasticities. Here, we examine progress in the molecular understanding of synaptic vesicle fusion and its control.

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Fig. 1: Calcium entry: location matters.
Fig. 2: The energy landscape of membrane fusion: the four hypothetical metastable states.

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Acknowledgements

The authors thank D. DiGregorio (Institut Pasteur) and J. Feigenson (Cornell University) for useful discussions. This work was supported by grants MH085783 (T.A.R.) and GM095674 (J.S.D.).

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Nature Reviews Neuroscience thanks K. Hirose and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA

    Jeremy S. Dittman & Timothy A. Ryan

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T.A.R. and J.S.D. made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission.

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Glossary

Isocalcium surfaces

Convenient graphical representations of the calcium concentration indicating regions that are at the same calcium levels similar to weather maps plotting regions at the same temperature (isotherms) or pressure (isobars).

Diffusion

The random migration of molecules or small particles arising from motion due to thermal energy.

Optical fluctuation analyses

Variant of noise analyses using a fluorescent reporter of calcium to monitor the trial-to-trial fluctuations in calcium levels following a stimulus-triggered calcium transient in order to count the number of calcium channels contributing to the fluorescence.

k BT

A natural unit of thermal energy available to drive nanoscale processes, defined by the product of the Boltzmann constant with absolute thermodynamic temperature (in Kelvin).

Arrhenius law

A rudimentary quantitative relationship between the microscopic rate constant of a transition between two states and the energy barrier (ΔE) separating the states: rate = A exp(−ΔE/kBT), where A is the pre-exponential factor, kB is the Boltzmann constant and T is the absolute thermodynamic temperature. The barrier height is commonly referred to as the activation energy.

SNARE

An acronym derived from soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor. The SNARE proteins comprise a deeply conserved protein family involved in membrane fusion in eukaryotes. The neuronal SNAREs responsible for synaptic vesicle fusion are syntaxin 1, SNAP25 and VAMP2.

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Dittman, J.S., Ryan, T.A. The control of release probability at nerve terminals. Nat Rev Neurosci 20, 177–186 (2019). https://doi.org/10.1038/s41583-018-0111-3

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