Volatile Anesthetics Bind Rat Synaptic Snare Proteins

Nägele, Peter; Mendel, J Brett; Placzek, William J.; Scott, Barbara A.; d’Avignon, D. André; Crowder, C. Michael

doi:10.1097/00000542-200510000-00015

Cited by 44 publications

(53 citation statements)

References 33 publications

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“…While anesthetic interactions with other SNARE and/or SNARE-related proteins are possible, our data raise the possibility that syntaxin 1A is involved in the response to isoflurane. This hypothesis is supported by NMR binding studies demonstrating the ability of isoflurane to bind to syntaxin monomers (Nagele et al 2005). It is currently unknown whether the md130A mutant is capable of supporting exocytosis, although replacing wild-type syntaxin with the md130A mutant produced C. elegans that were not viable; animals that had both md130A and wild-type syntaxin were viable and were resistant to isoflurane (van Swinderen et al 1999).…”

Section: Discussionmentioning

confidence: 94%

“…Behavioral sensitivity to isoflurane is significantly reduced in C. elegans heterozygous for the md130 mutation (van Swinderen et al 1999). In addition, isoflurane has been shown to bind to syntaxin 1A (Nagele et al 2005). To determine if md130A influences the isoflurane sensitivity of the mammalian neurotransmitter release machinery, PC12 cells were transfected with an md130A expression plasmid.…”

Section: Isoflurane Interacts With Syntaxin 1amentioning

confidence: 99%

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Isoflurane Inhibits the Neurotransmitter Release Machinery

Herring¹,

Xie²,

Marks³

et al. 2009

Journal of Neurophysiology

109

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Section: Discussionmentioning

confidence: 94%

Section: Isoflurane Interacts With Syntaxin 1amentioning

confidence: 99%

Isoflurane Inhibits the Neurotransmitter Release Machinery

Herring¹,

Xie²,

Marks³

et al. 2009

Journal of Neurophysiology

109

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“…anesthetics (42,43). Potential synaptic volatile anesthetic targets involved in regulating transmitter release include glutamate receptors, Na v channels (44), K 2P channels (45), nicotinic acetylcholine receptors (34), Ca v channels (46), neurotransmitter transporters (47,48), and SNARE proteins (8,49). Evidence suggests that the presynaptic effects of volatile anesthetics on neurotransmitter release are mediated by reduced nerve terminal excitability from inhibition of Na v channels rather than direct inhibition of Ca 2+ influx by inhibition of Ca v channels (7,44,50,51).…”

Section: Discussionmentioning

confidence: 99%

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

Baumgart

Zhou

Hara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

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Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca 2+ influx without significantly altering the Ca 2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca 2+ ] i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca 2+ ([Ca 2+ ] e ). Lowering external Ca 2+ to match the isoflurane-induced reduction in Ca 2+ entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca 2+ entry without significant direct effects on Ca 2+ -exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca 2+ influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system. GCaMP3 | pHlourin | mechanisms of anesthesia | live cell imaging | presynaptic T he molecular and cellular mechanisms of anesthetic-induced amnesia, unconsciousness and immobilization are incompletely understood, particularly for the modern halogenated ether derivatives like isoflurane. General anesthetics, which are essential to both medical practice and experimental neuroscience, have potent and selective effects on neurotransmission (1), including both presynaptic actions (reduced neurotransmitter release) and postsynaptic actions (modulation of receptor function). These effects contribute to anesthetic-induced reductions in neuronal interactions, which are critical to information processing and consciousness (2-4). Knowledge of the fundamental synaptic effects of anesthetics is therefore essential to a molecular and physiological understanding of anesthetic mechanisms, and to development of more selective and safer anesthetics.Although postsynaptic electrophysiological effects of anesthetics can be assessed directly using whole cell recordings and heterologous expression of putative molecular targets, their presynaptic actions have been difficult to resolve by conventional approaches that do not clearly discriminate between presynaptic and postsynaptic contributions. Direct evidence for presynaptic effects of volatile anesthetics includes selective inhibition of glutamate release from isolated nerve terminals (5, 6) and of synaptic vesicle (SV) exocytosis in intact hippocampal neurons (7). However, it remains controversial whether these effects involve direct inhibition of SV exocytosis itself or of upstrea...

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“…Published evidence has suggested that anesthetic interactions with SNAP-25 and/or G␤ 4 might contribute to depressed neuronal signaling. For example, SNAP-25, a component of the ternary SNARE complex, binds volatile anesthetics at physiologically relevant concentrations (24), and isoflurane and propofol inhibit neurotransmitter release through interactions with SNAREs or associated proteins (25,26). Mutagenesis in SNARE complex proteins (including SNAP-25) alters organism sensitivity to general anesthetics (27).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activation of Azipropofol Prolongs Anesthesia and Reveals Synaptic Targets

Weiser

Kelz

Eckenhoff

2013

Journal of Biological Chemistry

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Background: Azipropofol is a photoactive analog of the general anesthetic propofol. Results: In vivo photolabeling of tadpoles results in covalent ligand binding to neuronal proteins and prolongation of anesthesia. Conclusion: Reconciling time-resolved gel proteomics with behavioral state allows identification of potential anesthetic targets. Significance: In vivo activation of efficacious photolabels provides a novel approach to investigate mechanisms of general anesthesia.

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Volatile Anesthetics Bind Rat Synaptic Snare Proteins

Abstract: SNARE proteins are potential synaptic targets of volatile anesthetics.

Cited by 44 publications

References 33 publications

Isoflurane Inhibits the Neurotransmitter Release Machinery

Isoflurane Inhibits the Neurotransmitter Release Machinery

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

In Vivo Activation of Azipropofol Prolongs Anesthesia and Reveals Synaptic Targets

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Volatile Anesthetics Bind Rat Synaptic Snare Proteins

Abstract: SNARE proteins are potential synaptic targets of volatile anesthetics.

Cited by 44 publications

References 33 publications

Isoflurane Inhibits the Neurotransmitter Release Machinery

Isoflurane Inhibits the Neurotransmitter Release Machinery

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca 2+ influx, not Ca 2+ -exocytosis coupling

In Vivo Activation of Azipropofol Prolongs Anesthesia and Reveals Synaptic Targets

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Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling