title: Etomidate and propofol inhibit the neurotransmitter release machinery at different sites.
abstract: The mechanism of general anaesthetic action is only partially understood. Facilitation of inhibitory GABAA receptors plays an important role in the action of most anaesthetics, but is thought to be especially relevant in the case of intravenous anaesthetics, like etomidate and propofol. Recent evidence suggests that anaesthetics also inhibit excitatory synaptic transmission via a presynaptic mechanism(s), but it has been difficult to determine whether these agents act on the neurotransmitter release machinery itself. In the present study we sought to determine whether the intravenous anaesthetics propofol and etomidate inhibit the release machinery. For these studies we used an experimental approach that directly regulated [Ca2+]i at neurotransmitter release sites, thereby bypassing anaesthetic effects on channels and receptors in order to allow anaesthetic effects on the neurotransmitter release machinery to be examined in isolation. The data show that clinically relevant concentrations of propofol and etomidate inhibited the neurotransmitter release machinery in neurosecretory cells and in cultured hippocampal neurons. md130A is a mutant form of syntaxin with a truncated C-terminus. Overexpressing md130A in PC12 cells completely eliminated the reduction in neurotransmitter release produced by propofol, without affecting release itself. In contrast, overexpressing md130A in PC12 cells had little or no effect on the response to etomidate. These results suggest that both propofol and etomidate inhibit neurotransmitter release by a direct interaction with SNAREs and/or SNARE-associated proteins but they do so at different sites.
authors.affiliation: Department of Neurobiology, The University of Chicago, 5835 S. Cottage Grove Ave, Abbott Hall, Ab131, Chicago, IL 60637, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Herring
authors.forename: Kyle
authors.initials: K
authors.lastname: McMillan
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Pike
authors.forename: Jeremy
authors.initials: J
authors.lastname: Marks
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Fox
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xie
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol; D005045:Etomidate