Isoflurane modulates activation and inactivation gating of the prokaryotic Na+ channel NaChBac

Sand, Rheanna; Gingrich, Kevin J.; Macharadze, Tamar; Herold, Karl F.; Hemmings, Hugh C.

doi:10.1085/jgp.201611600

Cited by 31 publications

(30 citation statements)

References 51 publications

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“…Volatile anesthetics inhibit Na + currents in squid axons (Haydon and Urban, 1983) and at neuro-hypophysial terminals (Ouyang and Hemmings, 2005), as well as recombinant Na + channel currents (Rehberg et al, 1996;Sand et al, 2017). Isoflurane attenuates presynaptic AP amplitude at calyces of Held (Wu et al, 2004) and at neuro-hypophyseal terminals (Ouyang and Hemmings, 2005).…”

Section: Isoflurane Inhibits Presynaptic Voltage-gated Ion Channels Amentioning

confidence: 99%

Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms

et al. 2020

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Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of Significance Statement (64) Synaptic mechanisms of general anesthesia remain unidentified. In rat brainstem slices, isoflurane inhibits excitatory transmitter release by blocking presynaptic Ca 2+ channels and exocytic machinery, with the latter mechanism predominating in its inhibitory effect on high-frequency transmission. Both in slice and in vivo, isoflurane preferentially inhibits spike transmission induced by high-frequency presynaptic inputs. This low-pass filtering action of isoflurane likely plays a significant role in general anesthesia.

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Section: Isoflurane Inhibits Presynaptic Voltage-gated Ion Channels Amentioning

confidence: 99%

Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms

et al. 2020

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“…Volatile anesthetics including isoflurane also display activity-dependent inhibition of neuronal sodium channels in isolated rat neurophysical nerve terminals, 9 neuroblastoma cells, 24 and dorsal root ganglion neurons, 10 and in the bacterial voltage-gated sodium channels homologue voltagegated sodium channel of Bacillus halodurans, 39,40 but there was no pervious evidence that volatile anesthetics directly depress activity of excitatory neurons by inhibiting neuronal sodium channels.…”

Section: Perioperative Medicinementioning

confidence: 99%

Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice

et al. 2019

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Background: Volatile anesthetics inhibit presynaptic voltage-gated sodium channels to reduce neurotransmitter release, but their effects on excitatory neuron excitability by sodium current inhibition are unclear. The authors hypothesized that inhibition of transient and persistent neuronal sodium currents by the volatile anesthetic isoflurane contributes to reduced hippocampal pyramidal neuron excitability. Methods: Whole-cell patch-clamp recordings of sodium currents of hippocampal cornu ammonis pyramidal neurons were performed in acute mouse brain slices. The actions of isoflurane on both transient and persistent sodium currents were analyzed at clinically relevant concentrations of isoflurane. results: The median inhibitory concentration of isoflurane for inhibition of transient sodium currents was 1.0 ± 0.3 mM (~3.7 minimum alveolar concentration [MAC]) from a physiologic holding potential of −70 mV. Currents from a hyperpolarized holding potential of −120 mV were minimally inhibited (median inhibitory concentration = 3.6 ± 0.7 mM, ~13.3 MAC). Isoflurane (0.55 mM; ~2 MAC) shifted the voltage-dependence of steady-state inactivation by −6.5 ± 1.0 mV (n = 11, P < 0.0001), but did not affect the voltage-dependence of activation. Isoflurane increased the time constant for sodium channel recovery from 7.5 ± 0.6 to 12.7 ± 1.3 ms (n = 13, P < 0.001). Isoflurane also reduced persistent sodium current density (median inhibitory concentration = 0.4 ± 0.1 mM, ~1.5 MAC) and resurgent currents. Isoflurane (0.55 mM; ~2 MAC) reduced action potential amplitude, and hyperpolarized resting membrane potential from −54.6 ± 2.3 to −58.7 ± 2.1 mV (n = 16, P = 0.001). conclusions: Isoflurane at clinically relevant concentrations inhibits both transient and persistent sodium currents in hippocampal cornu ammonis pyramidal neurons. These mechanisms may contribute to reductions in both hippocampal neuron excitability and synaptic neurotransmission.

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“…These findings suggest conserved sites of interaction between isoflurane and the major neuronal Na v subtypes, which are highly homologous (Black and Waxman, 1996;Wood and Baker, 2001). Identification of their pharmacologically relevant binding site(s) should clarify whether volatile anesthetics interact with structurally homologous sites in Na v (Sand et al, 2017).…”

Section: Discussionmentioning

confidence: 90%

“…Isoflurane suppressed peak Na 1 current, produced a hyperpolarizing shift in the voltage dependence of fast inactivation, and slowed recovery from fast inactivation of brain Na v subtypes at a physiologically relevant membrane potential. These effects might involve more than one site of interaction of isoflurane with Na v since volatile anesthetics appear to have multiple sites of interaction with voltage-gated ion channels including Na v (Raju et al, 2013;Spurny et al, 2013;Sand et al, 2017). At a hyperpolarized holding potential, none of the Na v subtypes were inhibited by isoflurane, consistent with a low affinity of isoflurane for the resting state of Na v .…”

Section: Discussionmentioning

confidence: 91%

Differential Inhibition of Neuronal Sodium Channel Subtypes by the General Anesthetic Isoflurane

Zhou

Johnson

Herold

et al. 2019

J Pharmacol Exp Ther

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Volatile anesthetics depress neurotransmitter release in a brain region-and neurotransmitter-selective manner by unclear mechanisms. Voltage-gated sodium channels (Na v s), which are coupled to synaptic vesicle exocytosis, are inhibited by volatile anesthetics through reduction of peak current and modulation of gating. Subtype-selective effects of anesthetics on Na v might contribute to observed neurotransmitter-selective anesthetic effects on release. We analyzed anesthetic effects on Na 1 currents mediated by the principal neuronal Na v subtypes Na v 1.

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Isoflurane modulates activation and inactivation gating of the prokaryotic Na+ channel NaChBac

Cited by 31 publications

References 51 publications

Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms

Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms

Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice

Differential Inhibition of Neuronal Sodium Channel Subtypes by the General Anesthetic Isoflurane

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