Abstract
BackgroundThe 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.ResultsIn 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.ConclusionsThe 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.
Highlights
The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors
GABAC-ρ1 receptor (GABAC-ρ1R) heterologously expressed in oocytes generated typical non-desensitizing γ-aminobutyric acid (GABA) currents (Fig. 1a) when sulfur-containing compounds structurally related to taurine (SCC-tau) was perfused onto the same oocyte; Homo- and Hypo- elicited a response in a concentration dependent manner
It is well known that TPMPA competes with GABA for the same bindingsite, so since the IC50 of TPMPA values are similar; it is probable that SCC-tau, Homo and Hypo, share the same binding site as GABA in the G ABAC-ρ1R
Summary
The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. In the central nervous system (CNS) and retina, taurine is the second most abundant amino acid after glutamic acid, with a concentration in different species that ranges from 10 to 90 mM [3]. Taurine plays a role in different cell functions, as well as in neuronal migration and CNS development. Taurine is involved in other physiological processes of the CNS and retina, such as modulation of Ca2+ channels and neurotransmission [7,8,9,10,11]. GABA performs its inhibitory action via two types of receptors: (1) ionotropic, designated G ABAA and GABAC ( known as GABAA-ρ); and, (2) metabotropic, named GABAB, all of them with different molecular and pharmacological properties [12,13,14,15]. GABA performs its inhibitory action via two types of receptors: (1) ionotropic, designated G ABAA and GABAC ( known as GABAA-ρ); and, (2) metabotropic, named GABAB, all of them with different molecular and pharmacological properties [12,13,14,15]. GABAC receptor is interesting because it is insensitive to barbiturates, benzodiazepines, bicuculline, and baclofen (modulators and inhibitors of GABAA and G ABAB receptors, respectively) [16,17,18,19,20] but sensitive to picrotoxin and Methyl(1,2,5,6tetrahydropyridine-4-yl) phosphinic acid (TPMPA) [21]
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