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Differential modulation of human GABAC-?1 receptor by sulfur-containing compounds structurally related to taurine.

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-?1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABAC-?1R. RESULTS:In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABAC-?1R, 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-?1R 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.

SUBMITTER: Ochoa-de la Paz LD

PROVIDER: S-EPMC6076408 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Differential modulation of human GABA<sub>C</sub>-ρ1 receptor by sulfur-containing compounds structurally related to taurine.

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

BMC neuroscience 20180803 1

<h4>Background</h4>The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABA<sub>C</sub>-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<sub>C</sub>-ρ1R.<h4>Results</h4>In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed ...[more]

PMID: 30075755

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Project description:Background:The kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA). Methods:BPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin. Results:BPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination. Conclusions:BPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

Dataset Information

Differential modulation of human GABAC-?1 receptor by sulfur-containing compounds structurally related to taurine.

Publications

Differential modulation of human GABA<sub>C</sub>-ρ1 receptor by sulfur-containing compounds structurally related to taurine.

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