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Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming

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  • Marcial Camacho

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin
    Baylor College of Medicine)

  • Jayeeta Basu

    (Baylor College of Medicine
    Present address: Department of Neuroscience and Physiology, NYU Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA)

  • Thorsten Trimbuch

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin)

  • Shuwen Chang

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin)

  • Cristina Pulido-Lozano

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin)

  • Shwu-Shin Chang

    (Biochemistry and Pharmacology, University of Texas Southwestern Medical Center)

  • Irina Duluvova

    (Biochemistry and Pharmacology, University of Texas Southwestern Medical Center)

  • Masin Abo-Rady

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin)

  • Josep Rizo

    (Biochemistry and Pharmacology, University of Texas Southwestern Medical Center)

  • Christian Rosenmund

    (Institute of Neurophysiology, Charité—Universitätsmedizin Berlin
    NeuroCure Cluster of Excellence, Charité—Universitätsmedizin Berlin
    Baylor College of Medicine)

Abstract

The presynaptic active zone protein Munc13 is essential for neurotransmitter release, playing key roles in vesicle docking and priming. Mechanistically, it is thought that the C2A domain of Munc13 inhibits the priming function by homodimerization, and that RIM disrupts the autoinhibitory homodimerization forming monomeric priming-competent Munc13. However, it is unclear whether the C2A domain mediates other Munc13 functions in addition to this inactivation–activation switch. Here, we utilize mutations that modulate the homodimerization and heterodimerization states to define additional roles of the Munc13 C2A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C2A domain is critical for additional steps of vesicular release, including vesicle docking. Optimal vesicle docking and priming is only possible when Munc13 heterodimerizes with RIM via its C2A domain. Beyond being a switching module, our data suggest that the Munc13-RIM heterodimer is an active component of the vesicle docking, priming and release complex.

Suggested Citation

  • Marcial Camacho & Jayeeta Basu & Thorsten Trimbuch & Shuwen Chang & Cristina Pulido-Lozano & Shwu-Shin Chang & Irina Duluvova & Masin Abo-Rady & Josep Rizo & Christian Rosenmund, 2017. "Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15293
    DOI: 10.1038/ncomms15293
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