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Modulation of Ca(2+)-stimulated glutamate release from synaptosomes by Na+ entry through tetrodotoxin-sensitive channels.

ABSTRACT: Tityustoxin (TsTX), a toxin obtained from the venom of the Brazilian scorpion Tityus serrulatus, stimulates Na+ influx through tetrodotoxin (TTX)-sensitive Na+ channels which, in turn, promotes both Ca(2+)-dependent and Ca(2+)-independent release of glutamate from rat cerebrocortical synaptosomes. The level of Ca(2+)-dependent glutamate release after addition of 0.5 microM TsTX is greater than that produced by a maximally depolarizing concentration of KCl. This effect of TsTX, which is entirely dependent on Na+ entry, suggests that Na+ has a role in modulating Ca2+ entry and glutamate release that is not simply related to membrane depolarization. In order to investigate possible modulatory role(s) of Na+ on Ca(2+)-dependent glutamate release, we compared the effects of TsTX with those of KCl and the Na+ ionophore gramicidin D. When used alone, 100 nM gramicidin D produced a larger increase in intrasynaptosomal free Na+ than did 0.5 microM TsTX, and a similar rise in intrasynaptosomal free Ca2+, but was much less effective in promoting glutamate release. Even the combination of membrane depolarization (by 33 mM KCl) and elevation of intrasynaptosomal free Na+ (by 100 nM gramicidin) was still less effective than TsTX at causing Ca(2+)-dependent glutamate release. These data suggest that localized Na+ entry, through TTX-sensitive Na+ channels, exerts a modulatory role on Ca(2+)-dependent glutamate release from nerve endings in the cerebral cortex.

SUBMITTER: Romano-Silva MA

PROVIDER: S-EPMC1137500 | biostudies-other | 1994 Dec

REPOSITORIES: biostudies-other

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Project description:Small-diameter vesicular glutamate transporter 3-lineage (Vglut3lineage) dorsal root ganglion (DRG) neurons play an important role in mechanosensation and thermal hypersensitivity; however, little is known about their intrinsic electrical properties. We therefore set out to investigate mechanisms of excitability within this population. Calcium microfluorimetry analysis of male and female mouse DRG neurons demonstrated that the cooling compound menthol selectively activates a subset of Vglut3lineage neurons. Whole-cell recordings showed that small-diameter Vglut3lineage DRG neurons fire menthol-evoked action potentials and exhibited robust, transient receptor potential melastatin 8 (TRPM8)-dependent discharges at room temperature. This heightened excitability was confirmed by current-clamp and action potential phase-plot analyses, which showed menthol-sensitive Vglut3lineage neurons to have more depolarized membrane potentials, lower firing thresholds, and higher evoked firing frequencies compared with menthol-insensitive Vglut3lineage neurons. A biophysical analysis revealed voltage-gated sodium channel (NaV) currents in menthol-sensitive Vglut3lineage neurons were resistant to entry into slow inactivation compared with menthol-insensitive neurons. Multiplex in situ hybridization showed similar distributions of tetrodotoxin (TTX)-sensitive NaV transcripts between TRPM8-positive and -negative Vglut3lineage neurons; however, NaV1.8 transcripts, which encode TTX-resistant channels, were more prevalent in TRPM8-negative neurons. Conversely, pharmacological analyses identified distinct functional contributions of NaV subunits, with NaV1.1 driving firing in menthol-sensitive neurons, whereas other small-diameter Vglut3lineage neurons rely primarily on TTX-resistant NaV channels. Additionally, when NaV1.1 channels were blocked, the remaining NaV current readily entered into slow inactivation in menthol-sensitive Vglut3lineage neurons. Thus, these data demonstrate that TTX-sensitive NaVs drive action potential firing in menthol-sensitive sensory neurons and contribute to their heightened excitability.SIGNIFICANCE STATEMENT Somatosensory neurons encode various sensory modalities including thermoreception, mechanoreception, nociception, and itch. This report identifies a previously unknown requirement for tetrodotoxin-sensitive sodium channels in action potential firing in a discrete subpopulation of small-diameter sensory neurons that are activated by the cooling agent menthol. Together, our results provide a mechanistic understanding of factors that control intrinsic excitability in functionally distinct subsets of peripheral neurons. Furthermore, as menthol has been used for centuries as an analgesic and anti-pruritic, these findings support the viability of NaV1.1 as a therapeutic target for sensory disorders.

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Modulation of Ca(2+)-stimulated glutamate release from synaptosomes by Na+ entry through tetrodotoxin-sensitive channels.

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