Ochoa-de la Paz LD et al. (2018), Differential modulation of human GABAC-ρ1 recep...

XB-ART-55158

BMC Neurosci 2018 Aug 03;191:47. doi: 10.1186/s12868-018-0448-6.

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Differential modulation of human GABAC-ρ1 receptor by sulfur-containing compounds structurally related to taurine.

Ochoa-de la Paz LD , González-Andrade M , Pasantes-Morales H , Franco R , Zamora-Alvarado R , Zenteno E , Quiroz-Mercado H , Gonzales-Salinas R , Gulias-Cañizo R .

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BACKGROUND: The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABAC-ρ1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABAC-ρ1R. RESULTS: In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABAC-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 GABAC-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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Genes referenced: gabarap mapt

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	Fig. 1. Activation by GABA and SCC-tau of GABA-ρ1R heterologously expressed in oocytes. a Control: oocyte exposed to GABA at several concentrations (3–1000 µM); b–d Oocytes perfused with SCC-tau at the concentrations indicated. In each experiment the oocyte was first exposed to a GABA concentration equal to GABA’s EC50. The horizontal bars indicate the period of time when the compound was applicated. Oocytes were voltage-clamped at − 60 mV and inward currents are denoted as downward deflections. Chemical structure of GABA (a) and SCC-tau (b–d), are represent at right of each representative trace
	Fig. 2. GABA- and SCC-tau-induced currents in oocytes heterologously expressing GABAC-ρ1R. a Dose-response relationship showing the EC50 and Hill coefficient for each agonist. Data were normalized to the maximal current (I) obtained for each agonist. b Deactivation constant (τdeac) of currents activated by GABA, Hypo, and Homo. The difference in the deactivation constants between, GABA-, Hypo- or Homo-induced currents, was significant when P < 0.05. c Current–voltage relationship of GABA-, Homo-, and Hypo-induce currents at the indicated concentrations. Dose-response relationship (a) was constructed by measuring the maximum response evoked by each agonist concentration (see methods), for b and c, data are given as the mean ± S.E. from at least 8 oocytes (n = 8) from 3 frogs (N = 3)
	Fig. 3. Pharmacological modulation of GABA- and SCC-tau-induced currents by TPMPA (a) and picrotoxin (b). Currents were normalized to the maximum amplitude elicited by GABA or SCC-tau in absence of inhibitors. Data points are the mean ± S.E. from at least 7 oocytes (n = 7) from 3 frogs (N = 3)
	Fig. 4. Effect of Homo on GABA-induced currents in oocytes heterologously expressing GABAC-ρ1R. a Representative traces of currents induced by 1.5, 3, and 6 µM GABA and co-applied with Homo at the indicated concentrations. b Homo dose-response relation of currents elicited by 1.5, 3, and 6 µM GABA. The currents were normalized to the maximum amplitude elicited by the agonist in absence of modulators. Data points are the mean ± S.E. from at least 9 oocytes (n = 9) from 4 frogs (N = 4)
	Fig. 5. Effect of Hypo on GABA-induced currents in oocytes heterologously expressing GABAC-ρ1R. a Representative traces of currents induced by 1.5, 3, and 6 µM GABA and co-applied with Homo at the indicated concentrations. b Hypo dose-response relation of currents elicited by 1.5, 3, and 6 µM GABA. The currents were normalized to the maximum amplitude elicited by the agonist in absence of a modulator. Data points are the mean ± S.E. from at least 9 oocytes (n = 9) from 4 frogs (N = 4)
	Fig. 6. Structural models of GABAA side view (a) and top view (b) of the receptor and results of docking with different ligands, represented by colored spheres GABA (red circle), Tau-SCC (black circle), Hypo (orange circle), IA (violet circle), Homo (green circle), and Picro (brown circle). The structures were drawn using the PyMOL and LIGPLOT v.4.5.3 programs

References [+] :

Altschul, Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. 1997, Pubmed