Investigation of the modulation of glutamate release by sodium channels using neurotoxins

“…The similar inhibition potencies of isoflurane at two concentrations of VTD support a non-competitive mechanism, which suggests that inhibition does not involve direct competition at the VTD binding site. Although both VTD-evoked and TTX-sensitive 4AP-evoked release are Na v specific, the incomplete Ca 2+ dependence of VTD-evoked release (Bicalho et al, 2002) makes it an inferior model of depolarization-evoked transmitter release. On the other hand, 4AP induces transmitter release by mimicking action potential-evoked depolarizations (Tibbs et al, 1989), such that 4AP-evoked release models Na v -dependent transmitter release.…”

Section: Discussionmentioning

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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“…Different actions on sodium channels produce diverse consequences on neurotransmitter release that involve distinct presynaptic calcium channels, which supports the idea that sodium channels may modulate neurotransmitter release (22). Depending on the rate of increase in channel conductance, the outcome in terms of neurotransmitter release and calcium channel type coupled to that event is different (36).…”

Section: Discussionmentioning

confidence: 99%

Neurotransmitter evaluation in the hippocampus of rats after intracerebral injection of TsTX scorpion toxin

Nencioni¹,

Barreto²,

Lebrun³

et al. 2009

J. Venom. Anim. Toxins incl. Trop. Dis

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ABSTRACT:TsTX is an α-type sodium channel toxin that stimulates the discharge of neurotransmitters from neurons. In the present study we investigated which neurotransmitters are released in the hippocampus after TsTX injection and if they are responsible for electrographic or histopathological effects. Microdialysis revealed that the toxin increased glutamate extracellular levels in the hippocampus; however, levels of gamma-aminobutyric acid (GABA), glycine, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were not significantly altered. Neurodegeneration in pyramidal cells of hippocampus and electroencephalographic alterations caused by the toxin were blocked by pretreatment with riluzole, a glutamate release inhibitor. The present results suggest a specific activity of TsTX in the hippocampus which affects only glutamate release.

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Investigation of the modulation of glutamate release by sodium channels using neurotoxins

Cited by 29 publications

References 43 publications

Neuroprotective effect of Buyang Huanwu Decoction against focal cerebral ischemia/reperfusion injury in rats – Time window and mechanism

Neuroprotective effect of Buyang Huanwu Decoction against focal cerebral ischemia/reperfusion injury in rats – Time window and mechanism

Regional differences in the effects of isoflurane on neurotransmitter release

Neurotransmitter evaluation in the hippocampus of rats after intracerebral injection of TsTX scorpion toxin

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