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

Authors

• Lenin David Ochoa‑de la Paz, Universidad Nacional Autónoma de México & Asociación para Evitar la Ceguera en México I.A.P. HospitalFollow
• Martin González‑Andrade, Universidad Nacional Autónoma de México
• Herminia Pasantes‑Morales, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México
• Rodrigo Franco, University of Nebraska-LincolnFollow
• Rubén Zamora‑Alvarado, Asociación para Evitar la Ceguera en México I.A.P. Hospital
• Edgar Zenteno, Universidad Nacional Autónoma de México
• Hugo Quiroz‑Mercado, Asociación para Evitar la Ceguera en México I.A.P. Hospital
• Roberto Gonzales‑Salinas, Asociación para Evitar la Ceguera en México I.A.P. Hospital
• Rosario Gulias‑Cañizo, Asociación para Evitar la Ceguera en México I.A.P. Hospital

ORCID IDs

http://orcid.org/0000-0002-7561-0853

Document Type

Article

Date of this Version

2018

Citation

Ochoa‑de la Paz et al. BMC Neurosci (2018) 19:47 Page 1 of 11

Comments

The Author(s) 2018

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 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.