1. Departments of Neuroscience and,
2. Molecular Genetics, and,
3. Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
4. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence to: Jianyuan Sun^1,2Thomas C. Südhof^1,2,3 Correspondence and requests for materials should be addressed to J.S. (Email: Jianyuan.Sun@UTSouthwestern.edu) or T.C.S. (Email: Thomas.Sudhof@UTSouthwestern.edu).

Abstract

Ca²⁺-triggered synchronous neurotransmitter release is well described, but asynchronous release—in fact, its very existence—remains enigmatic. Here we report a quantitative description of asynchronous neurotransmitter release in calyx-of-Held synapses. We show that deletion of synaptotagmin 2 (Syt2) in mice selectively abolishes synchronous release, allowing us to study pure asynchronous release in isolation. Using photolysis experiments of caged Ca²⁺, we demonstrate that asynchronous release displays a Ca²⁺ cooperativity of 2 with a Ca²⁺ affinity of 44 M, in contrast to synchronous release, which exhibits a Ca²⁺ cooperativity of 5 with a Ca²⁺ affinity of 38 M. Our results reveal that release triggered in wild-type synapses at low Ca²⁺ concentrations is physiologically asynchronous, and that asynchronous release completely empties the readily releasable pool of vesicles during sustained elevations of Ca²⁺. We propose a dual-Ca²⁺-sensor model of release that quantitatively describes the contributions of synchronous and asynchronous release under conditions of different presynaptic Ca²⁺ dynamics.

1. Departments of Neuroscience and,
2. Molecular Genetics, and,
3. Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
4. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence to: Jianyuan Sun^1,2Thomas C. Südhof^1,2,3 Correspondence and requests for materials should be addressed to J.S. (Email: Jianyuan.Sun@UTSouthwestern.edu) or T.C.S. (Email: Thomas.Sudhof@UTSouthwestern.edu).

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