Modulation of taurine release by glutamate receptors and nitric oxide

Abstract

Taurine is held to function as a modulator and osmoregulator in the central nervous system, being of particular importance in the immature brain. In view of the possible involvement of excitatory pathways in the regulation of taurine function in the brain, the interference of glutamate receptors with taurine release from different tissue preparations in vitro and from the brain in vivo is of special interest. The release of taurine from the brain is enhanced by glutamate receptor agonists. This enhancement is inhibited by the respective receptor antagonists both in vitro and in vivo. The ionotropic N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor agonists appear to be the most effective in enhancing taurine release, their effects being receptor-mediated. Kainate is less effective, particularly in adults. Of the glutamate receptors, the NMDA class seems to be the most susceptible to modulation by nitric oxide. Nitric oxide also modulates taurine release, enhancing the basal release in both immature and mature hippocampus, whereas the K⁺-stimulated release is generally inhibited. Metabotropic glutamate receptors also participate in the regulation of taurine release, group I metabotropic glutamate receptors potentiating the release in the developing hippocampus, while group III receptors may be involved in the adult. Under various cell-damaging conditions, including ischemia, hypoxia and hypoglycemia, taurine release is enhanced, together with an enhanced release of excitatory amino acids. The increase in extracellular taurine upon excessive stimulation of glutamate receptors and under cell-damaging conditions may serve as an important protective mechanism against excitotoxicity, being particularly effective in the immature brain.

Introduction

Taurine (2-aminoethanesulfonic acid) is a phylogenetically ancient molecule and an almost ubiquitous cellular constituent throughout the animal kingdom (Huxtable, 1992). It is also one of the most abundant free amino acids in the brain. The concentration of taurine in the central nervous system (CNS) even exceeds that of glutamate during the ontogenic development of many mammals (Oja and Kontro, 1983). This simple sulfonic acid has been shown to be an essential nutrient for cats, and probably also for primates, especially during development (Sturman, 1993), an observation which has given impetus to taurine supplementation of infant formulas derived from taurine-poor cow milk. Taurine is known to act as an osmoregulator in marine animals (Simpson et al., 1959) and has also been considered to function in the same role in the brains of terrestrial species (Walz and Allen, 1987). On the other hand, taurine induces hyperpolarization and inhibits firing of central neurons and has been thought to act as a modulator of synaptic activity in the brain (Oja et al., 1977, Oja and Kontro, 1983, Saransaari and Oja, 1992).

Taurine differs from most other amino acids in being a sulfonic acid and a β-amino acid. The sulfonate group is a strong acid which renders taurine almost completely zwitterionic in the physiological pH range. For this reason taurine is highly water- and poorly lipid-soluble, which effectively hampers its diffusion through lipophilic membranes. The relatively voluminous sulfonyl group is apparently likewise a pure mechanical hindrance to diffusion. The saturable carrier-mediated Na⁺-dependent uptake mechanisms (Kontro and Oja, 1978a, Kontro and Oja, 1978b, Oja and Kontro, 1983) are therefore able to maintain relatively high taurine concentration gradients across plasma membranes also in neural cells (Huxtable, 1989), even though in microdialysis studies in vivo relatively high extracellular levels of taurine are encountered under certain experimental conditions (Lerma et al., 1986). The properties of taurine release in an experimental model, brain slices, and the pertinent literature with a comparison to γ-aminobutyrate (GABA) release were reviewed by the present authors in this series less than a decade ago (Saransaari and Oja, 1992). The reader is referred to this article with respect to an exhaustive review of the early studies on taurine release from brain slices in vitro.

We now update present knowledge of taurine release and focus on the interactions of glutamate receptors and nitric oxide (NO) in the release. Glutamate is the major excitatory transmitter in the CNS. Extracellular excitatory amino acids are neurotoxic in excess and the resulting overstimulation of their receptors contributes to neuronal death in certain neurological diseases and in ischemia. Massive release of excitatory amino acids from neural structures during ischemia and hypoxia has indeed been observed both in vitro (Pellegrini-Giampietro et al., 1990, Collard and Menon-Johansson, 1990, Ohkuma et al., 1995) and in vivo (Benveniste et al., 1984, Hagberg et al., 1985, Globus et al., 1988). On the other hand, the agonists of glutamate receptors have also been shown to evoke taurine release from cerebral cortical and hippocampal slices (Saransaari and Oja, 1991, Saransaari and Oja, 1997b). Taurine is able to protect neurons against the excitotoxicity evoked by glutamate and its congeners (French et al., 1986, Trenkner, 1990, Tang et al., 1986) and prevent harmful metabolic cascades induced by ischemia or hypoxia (Schurr et al., 1987). The interactions of glutamate receptors with taurine release are thus potentially of great functional significance.

Furthermore, glutamate receptors can foment the production of NO, a short-lived synaptic messenger in the CNS. NO is a Janus-faced compound in the nervous system, exhibiting both beneficial and detrimental properties which have not yet been fully explored and understood.