Diaminobutyric acid: A tool for discriminating between carrier-mediated and non-carrier-mediated release of GABA from synaptosomes?

Levi, Giulio; Rusca, Graziella; Raiteri, Maurizio

doi:10.1007/bf00965600

Cited by 29 publications

(17 citation statements)

References 17 publications

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“…The release induced by these conditions, as well as that induced by ouabain (see Fig. 2), seems to be carrier independent as it was not inhibited in DAB-treated synaptosomes (20,37). (iv) The fourth curve of Fig.…”

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confidence: 87%

“…(10,uM). with 2,4-diaminobutyric acid (DAB)t (20). Therefore, it does not appear to be carrier mediated (20 (20 and unpublished).…”

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confidence: 99%

“…with 2,4-diaminobutyric acid (DAB)t (20). Therefore, it does not appear to be carrier mediated (20 (20 and unpublished). It has been shown that the homoexchange of GABA has an apparent 1:1 stoichiometry in synaptosomes immersed in standard media containing low concentrations of GABA (<20-100 MM) (8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

“…Veratridine depolarizes synaptosomes by increasing the permeability of the Na+ channels (23). The rapid influx of Na+ t It is possible to discriminate between carrier-mediated and carrierindependent release of a given neurotransmitter by blocking its carrier-mediated transport with specific drugs (20)(21)(22). For GABA, the synaptosomes were treated with DAB during the incubation preceding superfusion.…”

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confidence: 99%

“…The treatment causes a strong and long-lasting inhibition of the GABA carrier. We considered as carrier-mediated those types of release that were inhibited in DAB-treated synaptosomes, and carrier-independent, those that were unaffected (20). caused by the drug is coupled to an influx of Ca2+ (23)(24)(25), while the intracellular K+ decreases (23,26).…”

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confidence: 99%

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Modulation of γ-aminobutyric acid transport in nerve endings: Role of extracellular γ-aminobutyric acid and of cationic fluxes

Levi

Raiteri

1978

Proc. Natl. Acad. Sci. U.S.A.

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The aim of the present study was to elucidate the possible functional significance of 'y-aminobutyric acid (GABA) homoexchange at nerve endings. Using synaptosomes from adult rat cerebrum, we found that a number of conditions altering cationic fluxes produced a concomitant change in the stoichiometry of GABA homoexchange, In fact, exogenous GABA (10 AM), while not causing net release of intrasynaptosomal GABA in standard conditions, triggered a large net GABA release in the presence of veratridine, Na+-K+-ATPase inhibitors, or the ionophore A23187, superimposed on that due to the various agents tested alone. This extra release was mediated by the membrane carrier, being largely inhibited by the GABA carrier-blocker L-diaminobutyric acid. The altered stoichiometry of GABA homoexchange observed under these conditions (efflux> influx) appeared to be coupled to the influx of Na+ (or of Ca2+), rather than determined by the establishment of a high intrasynaptosomal [Na+J Under conditions of reversed Na+ flux (Na+ efflux), the GABA outward/inward flux ratio was also reversed, and the stoichiometry of GABA homoexchange was in favor of net influx. The possible contribution of K+ to the effects observed is also discussed. It is concluded that the GABA transport system of nerve endings is susceptible to fine modulation by changes in cationic fluxes similar to those occurring in vivo during depolarization and repolarization. These fluxes may have a prominent role in determining the direction of net GABA transport in GABA-ergic nerve terminals of the living brain.The two essential steps of chemical neurotransmission are the depolarization-induced release of the transmitter from a presynaptic nerve ending and the rapid inactivation of the transmitter by specific biochemical mechanisms. The release of biogenic amines is generally considered to occur through an exocytotic-like process (1-5), and their inactivation mainly through specific reuptake mechanisms present in presynaptic nerve terminals (4, 6, 7). This scheme cannot be easily applied to neurotransmitter amino acids. For example, for 'y-aminobutyric acid (GABA), no evidence for an exocytotic release has been provided, and the mechanism of reuptake is still under discussion (8-15). In fact, several recent studies in vitro have shown that GABA transport consists essentially of a 1:1 homoexchange process in nerve endings incubated in standard media in the presence of low concentrations of the amino acid (9-14). This finding does not seem to fit with the high-affinity reuptake theory for inactivation of synaptically released GABA (4, 6, 16) and raises the question of the functional significance of a transport system that does not result in a net translocation of the substrate in one or the other direction.In the present study we have analyzed the relationship between GABA homoexchange and the processes of release and reuptake of the amino acid. On the basis of our results, we submit a hypothesis for GABA release and reuptake mechanisms and, in particular, we suggest...

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confidence: 87%

“…(10,uM). with 2,4-diaminobutyric acid (DAB)t (20). Therefore, it does not appear to be carrier mediated (20 (20 and unpublished).…”

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Modulation of γ-aminobutyric acid transport in nerve endings: Role of extracellular γ-aminobutyric acid and of cationic fluxes

Levi

Raiteri

1978

Proc. Natl. Acad. Sci. U.S.A.

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Neuro‐ and hepatic toxicological profile of (S)‐2,4‐diaminobutanoic acid in embryonic, adolescent and adult zebrafish

Ferraiuolo

Meister

Leckie

et al. 2019

J of Applied Toxicology

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(S)‐2,4‐Diaminobutanoic acid (DABA) is a noncanonical amino acid often co‐produced by cyanobacteria along with β‐N‐methylamino‐l‐alanine (BMAA) in algal blooms. Although BMAA is a well‐established neurotoxin, the toxicity of DABA remains unclear. As part of our development of biocompatible materials, we wish to make use of DABA as both a building block and as the end‐product of enzymatically induced depolymerization; however, if it is toxic at very low concentrations, this would not be possible. We examined the toxicity of DABA using both in vivo embryonic and adult zebrafish models. At higher sublethal concentrations (700 μm), the fish demonstrated early signs of cardiotoxicity. Adolescent zebrafish were able to tolerate a higher concentration. Post‐mortem histological analysis of juvenile zebrafish showed no liver or brain abnormalities associated with hepato‐ or neurotoxicity. Combined, these results show that DABA exhibits no overt toxicity at concentrations (100‐300 μm) within an order of magnitude of those envisioned for its application. This study further highlights the low cost and ease of using zebrafish as an early‐stage toxicological screening tool.

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Uptake, Exchange and Release of GABA in Isolated Nerve Endings

Levi

Banay‐Schwartz²,

Raiteri

1978

Amino Acids as Chemical Transmitters

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Diaminobutyric acid: A tool for discriminating between carrier-mediated and non-carrier-mediated release of GABA from synaptosomes?

Cited by 29 publications

References 17 publications

Modulation of γ-aminobutyric acid transport in nerve endings: Role of extracellular γ-aminobutyric acid and of cationic fluxes

Modulation of γ-aminobutyric acid transport in nerve endings: Role of extracellular γ-aminobutyric acid and of cationic fluxes

Neuro‐ and hepatic toxicological profile of (S)‐2,4‐diaminobutanoic acid in embryonic, adolescent and adult zebrafish

Uptake, Exchange and Release of GABA in Isolated Nerve Endings

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