Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic
Adekunle T. Bademosi,
James Steeves,
Shanker Karunanithi,
Oressia H. Zalucki,
Rachel S. Gormal,
Shu Liu,
Elsa Lauwers,
Patrik Verstreken,
Victor Anggono,
Frederic A. Meunier,
Bruno van Swinderen
Affiliations
Adekunle T. Bademosi
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
James Steeves
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Shanker Karunanithi
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; School of Medical Science and Menzies Health Institute Queensland, Griffith University Gold Coast Campus, Gold Coast QLD 4222, Australia
Oressia H. Zalucki
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Rachel S. Gormal
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Shu Liu
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Elsa Lauwers
VIB Center for Brain and Disease Research, KU Leuven Department of Neurosciences, Leuven Institute for Neuroscience and Disease (LIND), 3000 Leuven, Belgium
Patrik Verstreken
VIB Center for Brain and Disease Research, KU Leuven Department of Neurosciences, Leuven Institute for Neuroscience and Disease (LIND), 3000 Leuven, Belgium
Victor Anggono
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Frederic A. Meunier
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia
Bruno van Swinderen
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia; Corresponding author
Summary: 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. : Bademosi et al. use single-molecule imaging microscopy to understand how general anesthetics might affect presynaptic release mechanisms. They find that a clinically relevant concentration of propofol targets the presynaptic release machinery by specifically restricting syntaxin1A mobility on the plasma membrane. This suggests an alternate target process for these drugs. Keywords: super-resolution microscopy, sptPALM, propofol, etomidate, SNARE, Drosophila melanogaster, PC12, syntaxin1A, SNAP-25, neurotransmission
