Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential?

ABSTRACT

Taurine is a β-amino acid present in high concentrations in different areas of the mammalian central nervous system (CNS). It participates in different physiological processes such as osmoregulation, signal transduction, antioxidant activity, trophic factor activity, modulation of calcium movements and neurotransmission. It is known that taurine is an agonist of GABA_A receptors, and their affinity depends of the subunits that conform this receptor. GABA is the main inhibitory neurotransmitter of the CNS and exerts its effect through the activation of two types of specific receptors, called GABA_A and GABA_B. In the last years, changes in the expression pattern of the GABA_A receptors subunits has been related to pathologies, such as epilepsy, depression and alcoholism, among others. This changes in the GABA_A receptors conformation might be responsible of the loss in the effectiveness of the different drugs used in clinic protocols. Therefore, considering the physiological properties of taurine and the capacity to interact with GABA_A receptors conformed by different subunits combinations, it is clear their great potential for the design of new pharmacological strategies aimed to treat the pathologies where GABA has shown a relevant participation.

KEYWORDS:

• Taurine
• neurotransmitter receptors
• neurological diseases
• GABA-A receptors
• GABA-A subunits

1. Introduction

Taurine is a β-amino acid present in high concentrations in different tissues of mammals including all areas of the CNS. A deficiency of taurine during fetal life or lactation manifests itself as an embryonic and postnatal growth deficit and as several defects during development, and many of them related to the visual and nervous system. It participates in physiological processes such as osmoregulation and neurotransmission, among others. Initially, taurine was proposed as an inhibitory neurotransmitter; however, it is not considered a classic neurotransmitter because to date a specific receptor has not been identified, and its release is independent of Ca²⁺. Taurine exerts its neuronal inhibitory effect through the activation of GABA_A receptors (GABA_AR) but with less affinity than the specific agonists of each receptor [1]. Taurine has been used in different clinical trials as antiepileptic drug; in these protocols, one-third of the patients have shown a significant reduction of seizures by taurine medication. However, this effect is limited by the capacity to internalize the taurine into the brain under pathological conditions and the mechanism of taurine excretion by urine [2].

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mammalian CNS. GABA exerts its inhibitory effect through two types of specific receptors called GABA_A (ionotropic) and GABA_B (metabotropic). The complexity of GABA_A receptors lies in the number of subunits they have and in the different combinations in which they assemble, as well as in the variants generated by RNA splicing or editing [3]. To date, six α, three β, three γ, three ρ, and one δ, ε, π, and θ subunits have been characterized, which gives this receptor a high degree of heterogeneity. In general, GABA_AR are selectively blocked by bicuculline and picrotoxin, and they are allosterically modulated by neurosteroids, barbiturates, and benzodiazepines. The metabotropic GABA receptors (GABA_BR) are heterodimers composed of two subunits, GABA_BR1 and GABA_BR2. These receptors are mainly coupled to type G_iα and G_oα proteins, and they are insensitive to bicuculline but are inhibited by phaclofen. Despite their poor structural diversity, GABA_BR present a very varied kinetic and pharmacological response.

GABA_AR share its structural and functional properties with the family of ligand-gated ion channels, which include the glycine, acetylcholine, and serotonin receptors. It is known that some ligand-gated ion channels are regulated by molecules other than their specific agonists; for example, there is evidence of a direct modulation of the human GABA_A-ρ1 receptor by dopamine and serotonin [4].

2. Interaction of taurine with GABA receptors

Several reports indicate a role of GABA_AR in the inhibitory response of taurine in different regions of the brain such as hippocampus, cortex, and olfactory bulb. Experiments with recombinant GABA_A receptors reveal the ability of taurine to interact with receptors composed of different subunits. It is generally accepted that taurine is a weak agonist of GABA_AR; however, recent studies show that the effect of taurine depends essentially on the composition of GABA_AR. For example, receptors with α1 or α2 subunits have low affinity to taurine (EC₅₀ = 10 mM) [5], whereas receptors formed by α4, β2, and δ (thalamus) or α6, β2, and δ (hippocampus) subunits have a higher affinity to taurine with an EC₅₀ of 50 μM and 6 μM, respectively [6]. Apparently, the γ2 subunit regulates the efficacy of taurine gating in receptors that contain the α1 and α2 subunits [5]. In the case of GABA_A receptors formed by the ρ subunit (GABA_A-ρ), taurine activates the native GABA_A-ρ1 and GABA_A-ρ2 receptors in white perch bipolar cells [6] and modulates human cloned GABA_A-ρ1 receptors heterologously expressed in Xenopus laevis oocytes [7]. However, the receptors that include the ρ subunit in their conformation apparently are more sensitive to taurine and, in some cases, regulate the tonic current at sub-millimolar concentrations of taurine [8]. Interestingly, micromolar concentrations of taurine regulate the GABA-induced current, suggesting that both GABA and taurine act synergistically in extra-synaptic GABA receptors [7]. In the case of GABA_B receptors, the effect of taurine as an agonist is not yet clear; however, some experiments suggest that taurine activates this type of receptor with high affinity [9].

Some pathologies where GABA_AR have been involved are epilepsy, depression, and alcoholism, among others. A shared characteristic in these pathologies is an effect on the expression of the different subunits that make up the GABA_AR; for example, there is an apparent relationship between mutations in the γ2 subunit with the diagnosis of epilepsy in humans [10], and mutations in the δ subunit have been associated with some forms of congenital epilepsy in humans [11]. In the case of depression, studies show a deregulation of the β3, γ2, and δ subunits in the frontal cortex [12]. The post-mortem analysis by PCR of different brain regions in suicide victims with depression showed alterations in the α5, γ1, and γ2 subunits of the lateral dorsal zone of the prefrontal cortex and in the lateral inferior cortex [13]. Fatemi et al. [14] found an increase in the α2, α5, γ3, and ε subunits in the cerebellum of non-suicidal patients with depression. In humans, sequencing assays have identified alterations of different genes encoding α3, α2, γ1, and γ2 in the prefrontal cortex and hippocampus [15]. These results indicate a regulation in the expression of GABA_AR subunits specific to each region in the brain that is dependent on the time of exposure to ethanol.

Interestingly, these changes in the expression pattern of different subunits included those related to the taurine affinity in the GABA_AR. Thus, these changes in the composition of GABA_AR and consequently in affinity to taurine could generate relevant alterations in the physiology of receptor subpopulations.

3. Conclusions

GABA_AR present a structural variability due to the number of combinations of their different subunits; this provides different pharmacological properties in each receptor subtypes. This characteristic provides the potential for rational drug therapy in different disorders in which a GABAergic system is implicated, including epilepsy, depression, etc. The expression changes in the subunits, observed in these pathologies, alter the assembly of GABA_A receptors, modifying their binding affinity to the ligand and, consequently, its function. Therefore, probably, the different drugs used to treat these pathologies lose effectiveness, forcing the use of different combinations and the development of new drugs. In this sense, considering the inert, neuroprotective, and physiological characteristics of taurine, and in addition to the fact that it regulates the function of GABA receptors, there is clearly a great potential of this β-amino acid for the design of pharmacological strategies aimed to treat different pathologies where GABA has shown a relevant participation.

Author contributions

L Ochoa-de la Paz conceived the idea, coordinated and participated in the writing of the article. E Zenteno conceived the idea and participated in the writing of the article. R Gulias-Cañizo and H Quiroz-Mercado both participated in the writing of the article. All authors reviewed and revised the manuscript and provided their approval of the final version of the manuscript. All authors agree to be accountable for all aspects of the work.

Declaration of interest

L Ochoa-de la Paz is supported by grants PAPIIT-UNAM IA205918. E Zenteno is sponsored by Departamento de Bioquímica, Facultad dec Medicina, Universidad Nacional Autónoma de México. R Gulias-Cañizo is sponsored by Asociación para Evitar la Ceguera en México I.A.P Hospital Dr Luis Sánchez Bulnes. H Quiroz-Mercado is sponsored by Asociación para Evitar la Ceguera en México I.A.P Hospital Dr Luis Sánchez Bulnes. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was supported by grants PAPIIT-UNAM IA205918 and sponsorship by Asociación para Evitar la Ceguera en México I.A.P Hospital Dr Luis Sánchez Bulnes.