Regional differences in nerve terminal Na<sup>+</sup> channel subtype expression and Na<sup>+</sup> channel‐dependent glutamate and GABA release in rat CNS

Westphalen, Robert I.; Yu, Jin; Krivitski, Margarita; Jih, Ting-Yu; Hemmings, Hugh C.

doi:10.1111/j.1471-4159.2010.06722.x

Cited by 16 publications

(23 citation statements)

References 47 publications

(128 reference statements)

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“…Using this approach, 4AP-evoked release is significantly more sensitive to inhibition by volatile anesthetics as compared to KCl-evoked release, supporting a role for blockade of presynaptic Na + channels in the inhibitory effects of the anesthetics (Schlame and Hemmings, 1995; Westphalen and Hemmings, 2003). Interestingly, inhibition of glutamate release occurs with about 50% greater potency than inhibition of GABA release, consistent with pharmacologically relevant transmitter-specific specializations in neurotransmitter release regulation, perhaps involving differential coupling to Na + channels (Westphalen et al, 2010; Figure 4B). There is also evidence that volatile anesthetics inhibit neurotransmitter release in a brain region-specific manner (Westphalen et al, 2011), which suggests diversity in presynaptic Na + channel subtype expression and/or coupling to release (Westphalen et al, 2010).…”

Section: Na+ Channel Inhibition Leads To Inhibition Of Neurotransmittsupporting

confidence: 65%

“…Interestingly, inhibition of glutamate release occurs with about 50% greater potency than inhibition of GABA release, consistent with pharmacologically relevant transmitter-specific specializations in neurotransmitter release regulation, perhaps involving differential coupling to Na + channels (Westphalen et al, 2010; Figure 4B). There is also evidence that volatile anesthetics inhibit neurotransmitter release in a brain region-specific manner (Westphalen et al, 2011), which suggests diversity in presynaptic Na + channel subtype expression and/or coupling to release (Westphalen et al, 2010). …”

Section: Na+ Channel Inhibition Leads To Inhibition Of Neurotransmittsupporting

confidence: 65%

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Sodium Channels as Targets for Volatile Anesthetics

Herold¹,

Hemmings²

2012

Front. Pharmacol.

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The molecular mechanisms of modern inhaled anesthetics are still poorly understood although they are widely used in clinical settings. Considerable evidence supports effects on membrane proteins including ligand- and voltage-gated ion channels of excitable cells. Na+ channels are crucial to action potential initiation and propagation, and represent potential targets for volatile anesthetic effects on central nervous system depression. Inhibition of presynaptic Na+ channels leads to reduced neurotransmitter release at the synapse and could therefore contribute to the mechanisms by which volatile anesthetics produce their characteristic end points: amnesia, unconsciousness, and immobility. Early studies on crayfish and squid giant axon showed inhibition of Na+ currents by volatile anesthetics at high concentrations. Subsequent studies using native neuronal preparations and heterologous expression systems with various mammalian Na+ channel isoforms implicated inhibition of presynaptic Na+ channels in anesthetic actions at clinical concentrations. Volatile anesthetics reduce peak Na+ current (INa) and shift the voltage of half-maximal steady-state inactivation (h∞) toward more negative potentials, thus stabilizing the fast-inactivated state. Furthermore recovery from fast-inactivation is slowed, together with enhanced use-dependent block during pulse train protocols. These effects can depress presynaptic excitability, depolarization and Ca2+ entry, and ultimately reduce transmitter release. This reduction in transmitter release is more potent for glutamatergic compared to GABAergic terminals. Involvement of Na+ channel inhibition in mediating the immobility caused by volatile anesthetics has been demonstrated in animal studies, in which intrathecal infusion of the Na+ channel blocker tetrodotoxin increases volatile anesthetic potency, whereas infusion of the Na+ channels agonist veratridine reduces anesthetic potency. These studies indicate that inhibition of presynaptic Na+ channels by volatile anesthetics is involved in mediating some of their effects.

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Section: Na+ Channel Inhibition Leads To Inhibition Of Neurotransmittsupporting

confidence: 65%

Section: Na+ Channel Inhibition Leads To Inhibition Of Neurotransmittsupporting

confidence: 65%

Sodium Channels as Targets for Volatile Anesthetics

Herold¹,

Hemmings²

2012

Front. Pharmacol.

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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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“…Synaptosomes were prepared from adult (200–300 g) male Sprague-Dawley rat (Charles River Laboratories, Troy, NY) cerebral cortex, hippocampus, striatum or spinal cord (Westphalen and Hemmings, 2006a; Westphalen et al, 2010). Demyelinated synaptosomes were incubated with 5–10 nM L-[ 3 H]glutamate and 400–500 nM [ 14 C]GABA for 15 min at 30°C in 10 ml Krebs-HEPES buffer (KHB, composition in mM: NaCl 140, KCl 5, HEPES 20, MgCl 2 1, Na 2 HPO 4 1.2, NaHCO 3 5, EGTA 0.1, and D-glucose 10, pH 7.4 with NaOH).…”

Section: Methodsmentioning

confidence: 99%

Regional differences in the effects of isoflurane on neurotransmitter release

Westphalen¹,

Kwak²,

Daniels³

et al. 2011

Neuropharmacology

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Stimulus evoked neurotransmitter release requires that Na+ channel-dependent nerve terminal depolarization be transduced into synaptic vesicle exocytosis. Inhaled anesthetics block presynaptic Na+ channels and selectively inhibit glutamate over GABA release from isolated nerve terminals, indicating mechanistic differences between excitatory and inhibitory transmitter release. We compared the effects of isoflurane on depolarization-evoked [3H]glutamate and [14C]GABA release from isolated nerve terminals prepared from four regions of rat CNS evoked by 4-aminopyridine (4AP), veratridine (VTD), or elevated K+. These mechanistically distinct secretegogues distinguished between Na+ channel- and/or Ca2+ channel-mediated presynaptic effects. Isoflurane completely inhibited total 4AP-evoked glutamate release (IC50=0.42 ± 0.03 mM) more potently than GABA release (IC50=0.56 ± 0.02 mM) from cerebral cortex (1.3-fold greater potency), hippocampus and striatum, but inhibited glutamate and GABA release from spinal cord terminals equipotently. Na+ channel-specific VTD-evoked glutamate release from cortex was also significantly more sensitive to inhibition by isoflurane than was GABA release. Na+ channel-independent K+-evoked release was insensitive to isoflurane at clinical concentrations in all four regions, consistent with a target upstream of Ca2+ entry. Isoflurane inhibited Na+ channel-mediated (tetrodotoxin-sensitive) 4AP-evoked glutamate release (IC50=0.30 ± 0.03 mM) more potently than GABA release (IC50=0.67 ± 0.04 mM) from cortex (2.2-fold greater potency). The magnitude of inhibition of Na+ channel-mediated 4AP-evoked release by a single clinical concentration of isoflurane (0.35 mM) varied by region and transmitter: Inhibition of glutamate release from spinal cord was greater than from the three brain regions and greater than GABA release for each CNS region. These findings indicate that isoflurane selectively inhibits glutamate release compared to GABA release via Na+ channel-mediated transduction in the four CNS regions tested, and that differences in presynaptic Na+ channel involvement determine differences in anesthetic pharmacology.

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Regional differences in nerve terminal Na⁺ channel subtype expression and Na⁺ channel‐dependent glutamate and GABA release in rat CNS

Cited by 16 publications

References 47 publications

Sodium Channels as Targets for Volatile Anesthetics

Sodium Channels as Targets for Volatile Anesthetics

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

Regional differences in the effects of isoflurane on neurotransmitter release

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Regional differences in nerve terminal Na+ channel subtype expression and Na+ channel‐dependent glutamate and GABA release in rat CNS

Cited by 16 publications

References 47 publications

Sodium Channels as Targets for Volatile Anesthetics

Sodium Channels as Targets for Volatile Anesthetics

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

Regional differences in the effects of isoflurane on neurotransmitter release

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Regional differences in nerve terminal Na⁺ channel subtype expression and Na⁺ channel‐dependent glutamate and GABA release in rat CNS

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