Perhaps the most controversial hypothesis regarding the possible functions of NAA in the nervous system is the neuronal osmolyte hypothesis. It is controversial because this hypothesis has relatively little definitive experimental support, but paradoxically is one of the most cited hypotheses in recent NAA literature. In the 1960s, several research groups proposed, based on the high concentration of NAA in the brain, that it might function to counter the so-called "anion deficit" in neurons.3,4 In the 1990's, Taylor and colleagues proposed that NAA acts as a neuronal osmolyte involved in active neuronal volume regulation, or possibly in acid-base homeostasis.5 Using microdialysis, they demonstrated that NAA concentrations in the extracellular fluid increased in response to hypoosmotic stress.6 However, the changes in extracellular NAA concentrations were modest as compared with the substantially larger increases in extracellular taurine concentrations under the same conditions. Indeed, if NAA is involved significantly in neuronal osmoregulation, it is but one of many organic osmolytes that are responsible for maintaining water homeostasis in the brain. More recently, Davies et al. showed that under hypoosmotic conditions extracellular taurine levels increased almost 20 fold, whereas under the same conditions, extracellular NAA increased by only a few percent.7 NAA efflux of that magnitude could occur by simple leakage along the concentration gradient when neurons are subjected to osmotic stress. As such, NAA may be a minor contributor to neuronal volume regulation, whereas taurine and other osmolytes provide the predominant regulation of water homeostasis in the brain.
More recently, Baslow and colleagues have proposed a modified version of the neuronal osmolyte hypothesis in which NAA acts as a cotransport substrate for an as yet undescribed molecular water pump which removes excess metabolic water from neurons.8-10 The aspects of NAA that suggest that it could be involved in such a function include; 1) high concentration, 2) high intraneuronal to extracellular gradient, and 3) the fact that osmotic stress increases the extracellular NAA concentrations to a small degree (see chapter by Verbalis, this volume). Nonetheless, to date no proteins have been described in neurons that act to cotransport NAA and water out of neurons. However, it has been shown that the sodium-dependent NaDC3 transporter moves NAA into glial cells11 (also see chapter by Ganapathy and Fujita, this volume).
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