Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane

Westphalen, Robert I.; Desai, Kamlesh; Hemmings, Hugh C.

doi:10.1093/bja/aes448

Cited by 51 publications

(58 citation statements)

References 42 publications

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“…In rat neurohypophysial nerve terminal preparations, isoflurane inhibits Na + currents and dampens action potentials (44). This inhibition reduces neurotransmitter release (45)(46)(47)(48), which may play a critical role in mediating key physiological features of general anesthesia in vivo. In addition, Na V channel modulation may explain anesthetic agentinduced immobilization (19,20).…”

Section: Resultsmentioning

confidence: 99%

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

Barber

Carnevale

Klein

et al. 2014

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

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Halogenated inhaled general anesthetic agents modulate voltagegated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltagegated Na + (Na V ) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial Na V channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action.anesthesia | MD simulations | anesthetics | membrane proteins G eneral anesthetic agents have been in use for more than 160 y.However, we still understand relatively little about their mechanisms of action, which greatly limits our ability to design safer and more effective general anesthetic agents. Ion channels of the central nervous system are known to be key targets of general anesthetic agents, as their modulation can account for the endpoints and side effects of general anesthesia (1-4). Many families of ion channels are modulated by general anesthetic agents, including ligand-gated, voltage-gated, and nongated ion channels (2, 5-7). Mammalian voltage-gated Na + (Na V ) channels, which mediate the upstroke of the action potential, are regulated by numerous inhaled general anesthetic agents (8-14), which generally cause inhibition. Previous work showed that inhaled general anesthetic agents, including sevoflurane, isoflurane, desflurane, and halothane, mediate inhibition by increasing the rate of Na + channel inactivation, hyperpolarizing steady-state inactivation, and slowing recovery from inactivation (11,(15)(16)(17)(18). Inhibition of presynaptic Na V channels in the spinal cord is proposed to lead to inhibition of neurotransmitter release, facilitating immobilization-one of the endpoints of general anesthesia (14,19,20). Despite the importance of Na V channels as general anesthetic targets, little is known about interaction sites or the mechanisms of action.What is known about anesthetic sites in Na V channels comes primarily from the local anesthetic field. Local anesthetic agent binding to Na V channels is well characterized. These amphiphilic drugs enter the channel pore from the intracellular side, causing open-channel block (21). Investigating molecular mechanisms of mammalian Na V channel modulation by general anesthetic agents...

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Section: Resultsmentioning

confidence: 99%

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

Barber

Carnevale

Klein

et al. 2014

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

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“…Ca 2+ entry is regulated mainly by presynaptic ion channels (e.g., Na + , Ca 2+ , and K + channels), presynaptic receptors, and modulatory cell signaling mechanisms (25). We have shown previously that isoflurane has transmitter-specific effects on neurotransmitter release from a heterogeneous population of isolated axon terminals (26), and inhibits chemically evoked glutamate release more potently than release of other neurotransmitters (12,26). Pharmacological differences between glutamate and GABA release could result from synapse-specific differences in expression and/or coupling of specific isoforms of ion channels or other proteins regulating SV exocytosis (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…This discrepancy might be in part due to the use of permeabilized tumor cells to measure release of catecholamines, which is known to involve different mechanisms compared with typical small SVs, including distinct Ca 2+ sensitivity of SV vesicle exocytosis (56). Whether these differences represent transmitterspecific differences in release from large dense core vesicles in pheochromocytoma cells compared with release from small SVs in hippocampal neurons (26,55) or artifacts due to use of detergents and ionophores for membrane permeabilization (8,9) will require confirmation in intact catecholamine-releasing neurons using live cell imaging approaches. Our findings appear to contradict a report that isoflurane inhibits ionomycin-evoked RH414 destaining of rat hippocampal neuron boutons with no change in neuronal [Ca 2+ ] (9).…”

Section: Discussionmentioning

confidence: 99%

“…Cultured hippocampal neurons provide an accessible model for analyzing nerve terminal physiology, but they lack the tissue structure of slice preparations and therefore might not fully reflect properties of typical hippocampal neuron terminals in situ. Differences in isoflurane effects on SV exocytosis from other neuronal types and in other brain regions must also be considered (26).…”

Section: Discussionmentioning

confidence: 99%

“…Further studies are required to identify these molecular target(s) for isoflurane inhibition (26), but the studies presented here significantly narrow the list of possibilities. Volatile anesthetics have multiple cellular actions including depression of glutamate-mediated excitatory transmission and facilitation of inhibitory GABAergic transmission, in contrast to the principally GABAergic i.v.…”

Section: Discussionmentioning

confidence: 99%

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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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Explaining general anesthesia: A two‐step hypothesis linking sleep circuits and the synaptic release machinery

Swinderen

Kottler

2014

BioEssays

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Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two-step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non-sleeping systems can be made insensitive (or hypersensitive) to some anesthetics by modifying a single pre-synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep.

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Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane

Cited by 51 publications

References 42 publications

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

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

Explaining general anesthesia: A two‐step hypothesis linking sleep circuits and the synaptic release machinery

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Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane

Cited by 51 publications

References 42 publications

Modulation of a voltage-gated Na+channel by sevoflurane involves multiple sites and distinct mechanisms

Modulation of a voltage-gated Na+channel by sevoflurane involves multiple sites and distinct mechanisms

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

Explaining general anesthesia: A two‐step hypothesis linking sleep circuits and the synaptic release machinery

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Product

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Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

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