TY - JOUR
T1 - Differential modulation of human GABA C -ρ1 receptor by sulfur-containing compounds structurally related to taurine
AU - Ochoa-de la Paz, Lenin David
AU - González-Andrade, Martin
AU - Pasantes-Morales, Herminia
AU - Franco, Rodrigo
AU - Zamora-Alvarado, Rubén
AU - Zenteno, Edgar
AU - Quiroz-Mercado, Hugo
AU - Gonzales-Salinas, Roberto
AU - Gulias-Cañizo, Rosario
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/8/3
Y1 - 2018/8/3
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.
KW - GABA receptor
KW - Homotaurine
KW - Hypotaurine
KW - Isethionic acid
KW - Receptor modulation
KW - Sulfur-containing compounds
KW - Taurine
KW - Xenopus oocytes
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U2 - 10.1186/s12868-018-0448-6
DO - 10.1186/s12868-018-0448-6
M3 - Article
C2 - 30075755
AN - SCOPUS:85051089484
SN - 1471-2202
VL - 19
JO - BMC Neuroscience
JF - BMC Neuroscience
IS - 1
M1 - 47
ER -