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
Author Information
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. Electronic address: b.vanswinderen@uq.edu.au.
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.
