Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic
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Steeves, James
Karunanithi, Shanker
Zalucki, Oressia H
Gormal, Rachel S
Liu, Shu
Lauwers, Elsa
Verstreken, Patrik
Anggono, Victor
Meunier, Frederic A
van Swinderen, Bruno
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Abstract
Propofol is the most commonly used general anesthetic in humans. Our understanding of its mechanism of action has focused on its capacity to potentiate inhibitory systems in the brain. However, it is unknown whether other neural mechanisms are involved in general anesthesia. Here, we demonstrate that the synaptic release machinery is also a target. Using single-particle tracking photoactivation localization microscopy, we show that clinically relevant concentrations of propofol and etomidate restrict syntaxin1A mobility on the plasma membrane, whereas non-anesthetic analogs produce the opposite effect and increase syntaxin1A mobility. Removing the interaction with the t-SNARE partner SNAP-25 abolishes propofol-induced syntaxin1A confinement, indicating that syntaxin1A and SNAP-25 together form an emergent drug target. Impaired syntaxin1A mobility and exocytosis under propofol are both rescued by co-expressing a truncated syntaxin1A construct that interacts with SNAP-25. Our results suggest that propofol interferes with a step in SNARE complex formation, resulting in non-functional syntaxin1A nanoclusters.
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Cell Reports
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22
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2
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© 2017 The Author(s). This is an open access article under the CC BY-NC-ND license, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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Biochemistry and cell biology
Medical physiology
Medical physiology not elsewhere classified