Journal article
A novel region in the CaV2.1 α1 subunit C-terminus regulates fast synaptic vesicle fusion and vesicle docking at the mammalian presynaptic active zone
eLife, Vol.6, e28412
08/08/2017
DOI: 10.7554/eLife.28412
PMCID: PMC5548488
PMID: 28786379
Abstract
In central nervous system (CNS) synapses, action potential-evoked neurotransmitter release is principally mediated by CaV2.1 calcium channels (CaV2.1) and is highly dependent on the physical distance between CaV2.1 and synaptic vesicles (coupling). Although various active zone proteins are proposed to control coupling and abundance of CaV2.1 through direct interactions with the CaV2.1 α1 subunit C-terminus at the active zone, the role of these interaction partners is controversial. To define the intrinsic motifs that regulate coupling, we expressed mutant CaV2.1 α1 subunits on a CaV2.1 null background at the calyx of Held presynaptic terminal. Our results identified a region that directly controlled fast synaptic vesicle release and vesicle docking at the active zone independent of CaV2.1 abundance. In addition, proposed individual direct interactions with active zone proteins are insufficient for CaV2.1 abundance and coupling. Therefore, our work advances our molecular understanding of CaV2.1 regulation of neurotransmitter release in mammalian CNS synapses.
The points of contact between nerve cells are called synapses, and nerve cells communicate across synapses via chemicals known as neurotransmitters. These chemical messengers are initially stored within bubble-like packages called synaptic vesicles that are released after they fuse with the membrane of the nerve cell at a specialized site referred to as the “active zone”.Calcium ions are one of the major factors that lead to the release of synaptic vesicles. Ion channel proteins in the membrane of the nerve cell control the flow of calcium ions into the cell. There are often many different ion channels at a synapse, but one type called CaV2.1 most effectively triggers the release of synaptic vesicles when a nerve impulse reaches the synapse. Various proteins at the active zone can bind directly to parts of the CaV2.1 channel that are identified by a short sequence of amino acids – the building blocks of all proteins. Several researchers have proposed that the interactions with some of these short sequences, which are also known as motifs, control how much of this ion channel is in the synapse and how it interacts with synaptic vesicles to regulate the release of neurotransmitters. However, other researchers do not agree with this proposed explanation.Lübbert, Goral et al. set out to determine which parts in a specific part of the CaV2.1 channel (called the “α1 subunit C-terminus”) are critical for its interaction with synaptic vesicles. The experiments revealed a new motif that regulates how many synaptic vesicles could be released in response to electrical impulses travelling along nerve cells from mice. The same motif also regulates the total number of synaptic vesicles at the active zone.Lübbert, Goral et al. went on to show that binding to known active proteins at most played a minor role in controlling the abundance of the CaV2.1 channels and how close they were to the synaptic vesicles. As such, these findings counter prevailing views of the roles of certain motifs in the α1 subunit of the CaV2.1 channel. Thus, it may be necessary to re-think how the CaV2.1 channel regulates the release of synaptic vesicles.Ion channels are vital to the activity of all nerve cells, and working out how the numbers and organization of CaV2.1 and related ion channels are regulated will be fundamental to understanding how information is encoded in brain. In addition, problems with these kinds of ion channel may result in disorders such as migraines and epilepsy. Therefore, the new findings may help to guide further studies investigating possible ways to treat these disorders.
Details
- Title: Subtitle
- A novel region in the CaV2.1 α1 subunit C-terminus regulates fast synaptic vesicle fusion and vesicle docking at the mammalian presynaptic active zone
- Creators
- Matthias Lübbert - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, United StatesR Oliver Goral - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, United States, Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United StatesRachel Satterfield - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, United StatesTravis Putzke - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, United StatesArn MJM van den Maagdenberg - Departments of Human Genetics and Neurology, Leiden University Medical Center, Leiden, NetherlandsNaomi Kamasawa - Max Planck Florida Electron Microscopy Core, Max Planck Florida Institute for Neuroscience, Jupiter, United StatesSamuel M Young - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, United States, Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States, Department of Otolaryngology, University of Iowa, Iowa City, United States, Iowa Neuroscience Institute, University of Iowa, Iowa City, United States, Aging Mind Brain Initiative, University of Iowa, Iowa City, United States
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.6, e28412
- DOI
- 10.7554/eLife.28412
- PMID
- 28786379
- PMCID
- PMC5548488
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Grant note
- DOI: 10.13039/100000055, name: National Institute on Deafness and Other Communication Disorders, award: R01 DC014093; DOI: 10.13039/501100004189, name: Max-Planck-Gesellschaft
- Language
- English
- Date published
- 08/08/2017
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Otolaryngology
- Record Identifier
- 9984025347002771
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