On the mechanism by which veratridine causes a calcium-independent release of gamma-aminobutyric acid from brain slices.
1 The mechanisms by which veratridine increases the release of gamma-aminobutyric acid (GABA) from brain slices have been studied.2 Exposure of superfused cerebro-cortical, nigral or cerebellar slices to veratridine (5 muM) or KCl (50 mM) caused large increases in the efflux of [(3)H]-GABA.3 Reduction of the external Ca concentration [Ca](o) to zero had strikingly different effects on the veratridine and K-evoked release of [(3)H]-GABA. The K-evoked release from all three areas was greatly reduced in Ca-free medium, but the veratridine-evoked release from cerebeller slices was not affected, and the release of [(3)H]-GABA from cortical and nigral slices was increased three fold. The potentiation of the veratridine evoked release of GABA which occurred in Ca-free medium was not due to the reduction in divalent ions, because it still occurred in medium in which the Ca was replaced by an equivalent amount of Mg.4 The veratridine-evoked release of [(14)C]-glycine from slices of spinal cord was also significantly increased in Ca-free medium. In contrast, the release of cortical [(3)H]-noradrenaline and [(14)C]-acetylcholine caused by the alkaloid was greatly diminished in Ca-free medium.5 The veratridine but not the K-evoked release of [(3)H]-GABA was abolished when the external Na concentration [Na](o) was reduced to zero and by tetrodotoxin (TTX) (0.2 muM). Cl-free medium did not affect the veratridine-evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.6 Exposure of the tissue to depolarizing concentrations of external K ([K](o) = 120 mM) did not abolish the veratridine evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.7 Pre-incubation of cortical slices with L-2,4, diaminobutyric acid (DABA), or substitution of Na in the superfusion medium with Li, did not affect the veratridine-evoked release of [(3)H]-GABA, indicating that the alkaloid does not stimulate GABA efflux by a carrier-mediated transport process.8 Exposure of the tissue to ruthenium red (10 muM) increased the veratridine evoked release of [(3)H]-GABA in both normal and in Ca-free medium but almost abolished the K-evoked release.9 It is suggested that veratridine causes GABA release by increasing the permeability of the nerve terminals to Na. In normal medium, the resulting influx of Ca(2+) ions through voltage-dependent Ca(2+) channels may be involved in triggering the release of GABA. However, a major part of the GABA efflux appears to be triggered by the release of Ca(2+) ions from intraterminal mitochondria, which results from the increase in[Na](i). Since Ca(2+) ions antagonize the action of veratridine, the potentiation of the drug-evoked release of GABA that occurs in Ca-free medium, might be due to the absence of the antagonistic Ca(2+) ions. The resulting greater increase in Na entry and [Ca](i) caused by Ca release from intracellular stores, must presumably more than balance the contribution normally made by any influx of extracellular Ca(2+).
D000109:Acetylcholine / Q000378:metabolism; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology*; D002712:Chlorides / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology*; D014702:Veratrine / Q000031:analogs & derivatives*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000613:Aminobutyrates; D002712:Chlorides; D012430:Ruthenium Red; C005959:2,4-diaminobutyric acid; D005680:gamma-Aminobutyric Acid; D014701:Veratridine; D008094:Lithium; D012964:Sodium; D014702:Veratrine; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium; D005998:Glycine; D009638:Norepinephrine