Pathofunctional roles of glutamine transporters in neurotransmission, insulin secretion and pH regulation
Glutamine is involved in many metabolic pathways such as generation of amino acids, nucleotides and glutathione. Glutamine also serves in pH homeostasis, urea formation, immune response and wound healing. In addition, glutamine is considered to be the primary precursor of the fast neurotransmitters glutamate and GABA in the central nervous system (CNS). The prevailing hypothesis of a glutamate/GABA-glutamine cycle suggests that a large amount of released glutamate and GABA are translocated into perisynaptic astroglial cells, converted into glutamine, and subsequently shuttled back to neurons for regeneration of the neurotransmitters. This mechanistic view is supported by differential localization of glutamate and GABA transporters on perisynaptic glial processes, and demonstration of the key glutamine metabolizing enzymes glutamine synthetase (GS) and phosphate-activated glutaminase (PAG) in glial cells and nerve terminals, respectively. However, the molecular mechanisms involved in glutamine extrusion from glial cells and its transport into neurons have until recently eluded characterization. We have molecularly identified a family of amino acid transporters (Slc38) with isoform specific characteristics. We show that the system A transporters (SATs) mediate neuronal transport of glutamine. SAT1 is enriched in GAD67 expressing GABAergic neurons suggesting a role in GABA formation. SAT2 expression is pronounced in the somatodendritic domains of glutamatergic neurons where it sustains formation of glutamate and is intrinsic for retrograde signaling. Activity of the homologous system N transporter SN1 – expressed exclusively on astroglial cell membranes – is dynamically regulated by intracellular protein kinases and may fine-tune extracellular levels of glutamine accessible for neuronal uptake. SN2 – also expressed in the astroglial cells, but with differential subcellular localization – mediates glutamine release for neurotransmitter synthesis and glycine release to regulate NMDA receptors. Finally, we have shown that these transporters also contribute to pH restoration during chronic metabolic acidosis and regulation of insulin secretion. Recently, I have also contributed to the investigation of a child with congenital glutamine synthetase deficiency, who developed generalized hypotonia and hyperreflexia and treatment-resistant seizures postpartum and had very low serum and cerebrospinal fluid concentrations of glutamine and glutamate (Häberle et al. 2012). Glutamine supplementation restored serum levels of glutamine and glutamate, while corresponding values in the CNS approached normal. Ammonia toxicity was also prevented. The frequency of seizures abated and EEG showed significant improvement. Altogether, our data show the importance of glutamine and glutamine transporters in normal physiology and pathophysiology and bolster existence of a glutamate/GABA-glutamine cycle.