Volatile anesthetics bind rat synaptic snare proteins

Academic Article

Abstract

  • Background: Volatile general anesthetics (VAs) have a number of synaptic actions, one of which is to inhibit excitatory neurotransmitter release; however, no presynaptic VA binding proteins have been identified. Genetic data in Caenorhabditis elegans have led to the hypothesis that a protein that interacts with the presynaptic protein syntaxin 1A is a VA target. Motivated by this hypothesis, the authors measured the ability of syntaxin 1A and proteins that interact with syntaxin to bind to halothane and isoflurane. Methods: Recombinant rat syntaxin 1A, SNAP-25B, VAMP2, and the ternary SNARE complex that they form were tested. Binding of VAs to these proteins was detected by 19F-nuclear magnetic resonance relaxation measurements. Structural alterations in the proteins were examined by circular dichroism and ability to form complexes. Results: Volatile anesthetics did not bind to VAMP2. At concentrations in the clinical range, VAs did bind to SNAP-25B; however, binding was detected only in preparations containing SNAP-25B homomultimers. VAs also bound at clinical concentrations to both syntaxin and the SNARE complex. Addition of an N-terminal His6 tag to syntaxin abolished its ability to bind VAs despite normal secondary structure and ability to form SNARE complexes; thrombin cleavage of the tag restored VA binding. Thus, the VA binding site(s) has structural requirements and is not simply any α-helical bundle. VAs at supraclinical concentrations produced an increase in helicity of the SNARE complex; otherwise, VA binding produced no gross alteration in the stability or secondary structure of the SNARE complex. Conclusion: SNARE proteins are potential synaptic targets of volatile anesthetics. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
  • Published In

  • Anesthesiology  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 2268482
  • Author List

  • Nagele P; Mendel JB; Placzek WJ; Scott BA; D'Avignon DA; Crowder CM
  • Start Page

  • 768
  • End Page

  • 778
  • Volume

  • 103
  • Issue

  • 4