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

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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.

Electronic supplementary material

The online version of this article (10.1186/s12868-018-0448-6) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Lenin David Ochoa-de la Paz:

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

(+52 55) 5623-2510 , (+52 55) 5659-6572 , lochoa@unam.mx

Martin González-Andrade: martin.andrade@unam.mx

Herminia Pasantes-Morales: hpasante@ifc.unam.mx

Rodrigo Franco: rodrigo.franco@unl.edu

Rubén Zamora-Alvarado: rubenzam@gmail.com

Edgar Zenteno: ezenteno@unam.mx

Hugo Quiroz-Mercado: hugoquiroz@yahoo.com.mx

Roberto Gonzales-Salinas: dr.gonzalezsalinas@gmail.com

Rosario Gulias-Cañizo: rosario.gulias@apec.com.mx

Journal

Journal ID (nlm-ta): BMC Neurosci

Journal ID (iso-abbrev): BMC Neurosci

Title: BMC Neuroscience

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2202

Publication date (Electronic): 3 August 2018

Publication date PMC-release: 3 August 2018

Publication date Collection: 2018

Volume: 19

Electronic Location Identifier: 47

Affiliations

[1 ]ISNI 0000 0001 2159 0001, GRID grid.9486.3, Departamento de Bioquímica, Facultad de Medicina, , Universidad Nacional Autónoma de México, ; Avenida Universidad 3000, Copilco Universidad, Cd. Universitaria, 04510 México City, México

[2 ]Departamento de Investigación APEC, Asociación para Evitar la Ceguera en México I.A.P. Hospital Dr. Luis Sánchez Bulnes, Fernández Leal 60, Col. La Concepción Coyoacán, 04020 Mexico City, Mexico

[3 ]ISNI 0000 0001 2159 0001, GRID grid.9486.3, División de Neurociencias, Instituto de Fisiología Celular, , Universidad Nacional Autónoma de México, ; Circuito Exterior s/n, Coyoacán, Ciudad Universitaria, 04510 Mexico City, Mexico

[4 ]ISNI 0000 0004 1937 0060, GRID grid.24434.35, Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences, , University of Nebraska-Lincoln, ; Lincoln, NE 68583 USA

Author information

Lenin David Ochoa-de la Paz http://orcid.org/0000-0002-7561-0853

Article

Publisher ID: 448

DOI: 10.1186/s12868-018-0448-6

PMC ID: 6076408

PubMed ID: 30075755

SO-VID: d7b78f68-fd65-4ead-ae87-46f2a04966e9

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 February 2018

Date accepted : 27 July 2018

Funding

Funded by: PAPIIT-UNAM IA208116

Award ID: IA208116

Award Recipient : Lenin David Ochoa-de la Paz

Funded by: PAPIIT-UNAM IA205918

Award ID: IA204126

Award Recipient : Lenin David Ochoa-de la Paz

Funded by: LANCAD-UNAM-DGTIC-313

Funded by: Departamento de Investigación APEC

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: receptor modulation,gaba receptor,xenopus oocytes,sulfur-containing compounds,taurine,homotaurine,hypotaurine,isethionic acid

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: receptor modulation, gaba receptor, xenopus oocytes, sulfur-containing compounds, taurine, homotaurine, hypotaurine, isethionic acid