Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine

Lenin David Ochoa-de la Paz, Martin González-Andrade, Herminia Pasantes-Morales, Rodrigo Franco-Cruz, Rubén Zamora-Alvarado, Edgar Zenteno, Hugo Quiroz-Mercado, Roberto Gonzales-Salinas, Rosario Gulias-Cañizo

Research output: Contribution to journalArticle

Abstract

Background: The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABA C -ρ1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABA C -ρ1R. Results: In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABA C -ρ1R, showing an increment in its deactivation time with no changes in channel permeability, whereas isethionic acid showed no effect. Competitive assays suggest that hypotaurine and homotaurine compete for the GABA-binding site. In addition, their effects were blocked by the ion-channel blockers picrotixin and Methyl(1,2,5,6-tetrahydropyridine-4-yl) phosphinic acid. In contrast to taurine, co-application of GABA with hypotaurine or homotaurine revealed that the dual effect is present separately for each compound: hypotaurine modulates positively the GABA current, while homotaurine shows a negative modulation, both in a dose-dependent manner. Interestingly, homotaurine diminished hypotaurine-induced currents. Thus, these results strongly suggest a competitive interaction between GABA and homotaurine or hypotaurine for the same binding site. "In silico" modeling confirms these observations, but it also shows a second binding site for homotaurine, which could explain the negative effect of this compound on the current generated by GABA or hypotaurine, during co-application protocols. Conclusions: The sulfur-containing compounds structurally related to taurine are partial agonists of GABA C -ρ1R that occupy the agonist binding site. The dual effect is unique to taurine, whereas in the case of hypotaurine and homotaurine it presents separately; hypotaurine increases and homotaurine decreases the GABA current.

Original languageEnglish (US)
Article number47
JournalBMC Neuroscience
Volume19
Issue number1
DOIs
StatePublished - Aug 3 2018

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Sulfur Compounds
Taurine
gamma-Aminobutyric Acid
Isethionic Acid
Binding Sites
Phosphinic Acids
GABA-C receptor
hypotaurine
tramiprosate
GABA Agonists
Neurotransmitter Receptor
Xenopus laevis
Ion Channels
Computer Simulation
Oocytes
Permeability
Amino Acids

Keywords

  • GABA receptor
  • Homotaurine
  • Hypotaurine
  • Isethionic acid
  • Receptor modulation
  • Sulfur-containing compounds
  • Taurine
  • Xenopus oocytes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

Ochoa-de la Paz, L. D., González-Andrade, M., Pasantes-Morales, H., Franco-Cruz, R., Zamora-Alvarado, R., Zenteno, E., ... Gulias-Cañizo, R. (2018). Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine BMC Neuroscience, 19(1), [47]. https://doi.org/10.1186/s12868-018-0448-6

Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine . / Ochoa-de la Paz, Lenin David; González-Andrade, Martin; Pasantes-Morales, Herminia; Franco-Cruz, Rodrigo; Zamora-Alvarado, Rubén; Zenteno, Edgar; Quiroz-Mercado, Hugo; Gonzales-Salinas, Roberto; Gulias-Cañizo, Rosario.

In: BMC Neuroscience, Vol. 19, No. 1, 47, 03.08.2018.

Research output: Contribution to journalArticle

Ochoa-de la Paz, LD, González-Andrade, M, Pasantes-Morales, H, Franco-Cruz, R, Zamora-Alvarado, R, Zenteno, E, Quiroz-Mercado, H, Gonzales-Salinas, R & Gulias-Cañizo, R 2018, ' Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine ', BMC Neuroscience, vol. 19, no. 1, 47. https://doi.org/10.1186/s12868-018-0448-6
Ochoa-de la Paz, Lenin David ; González-Andrade, Martin ; Pasantes-Morales, Herminia ; Franco-Cruz, Rodrigo ; Zamora-Alvarado, Rubén ; Zenteno, Edgar ; Quiroz-Mercado, Hugo ; Gonzales-Salinas, Roberto ; Gulias-Cañizo, Rosario. / Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine In: BMC Neuroscience. 2018 ; Vol. 19, No. 1.
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AU - Ochoa-de la Paz, Lenin David

AU - González-Andrade, Martin

AU - Pasantes-Morales, Herminia

AU - Franco-Cruz, Rodrigo

AU - Zamora-Alvarado, Rubén

AU - Zenteno, Edgar

AU - Quiroz-Mercado, Hugo

AU - Gonzales-Salinas, Roberto

AU - Gulias-Cañizo, Rosario

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N2 - Background: The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABA C -ρ1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABA C -ρ1R. Results: In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABA C -ρ1R, showing an increment in its deactivation time with no changes in channel permeability, whereas isethionic acid showed no effect. Competitive assays suggest that hypotaurine and homotaurine compete for the GABA-binding site. In addition, their effects were blocked by the ion-channel blockers picrotixin and Methyl(1,2,5,6-tetrahydropyridine-4-yl) phosphinic acid. In contrast to taurine, co-application of GABA with hypotaurine or homotaurine revealed that the dual effect is present separately for each compound: hypotaurine modulates positively the GABA current, while homotaurine shows a negative modulation, both in a dose-dependent manner. Interestingly, homotaurine diminished hypotaurine-induced currents. Thus, these results strongly suggest a competitive interaction between GABA and homotaurine or hypotaurine for the same binding site. "In silico" modeling confirms these observations, but it also shows a second binding site for homotaurine, which could explain the negative effect of this compound on the current generated by GABA or hypotaurine, during co-application protocols. Conclusions: The sulfur-containing compounds structurally related to taurine are partial agonists of GABA C -ρ1R that occupy the agonist binding site. The dual effect is unique to taurine, whereas in the case of hypotaurine and homotaurine it presents separately; hypotaurine increases and homotaurine decreases the GABA current.

AB - Background: The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABA C -ρ1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABA C -ρ1R. Results: In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABA C -ρ1R, showing an increment in its deactivation time with no changes in channel permeability, whereas isethionic acid showed no effect. Competitive assays suggest that hypotaurine and homotaurine compete for the GABA-binding site. In addition, their effects were blocked by the ion-channel blockers picrotixin and Methyl(1,2,5,6-tetrahydropyridine-4-yl) phosphinic acid. In contrast to taurine, co-application of GABA with hypotaurine or homotaurine revealed that the dual effect is present separately for each compound: hypotaurine modulates positively the GABA current, while homotaurine shows a negative modulation, both in a dose-dependent manner. Interestingly, homotaurine diminished hypotaurine-induced currents. Thus, these results strongly suggest a competitive interaction between GABA and homotaurine or hypotaurine for the same binding site. "In silico" modeling confirms these observations, but it also shows a second binding site for homotaurine, which could explain the negative effect of this compound on the current generated by GABA or hypotaurine, during co-application protocols. Conclusions: The sulfur-containing compounds structurally related to taurine are partial agonists of GABA C -ρ1R that occupy the agonist binding site. The dual effect is unique to taurine, whereas in the case of hypotaurine and homotaurine it presents separately; hypotaurine increases and homotaurine decreases the GABA current.

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KW - Isethionic acid

KW - Receptor modulation

KW - Sulfur-containing compounds

KW - Taurine

KW - Xenopus oocytes

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