Glycine Transporters and Its Coupling with NMDA Receptors

Abstract

Glycine plays two roles in neurotransmission. In caudal areas like the spinal cord and the brainstem, it acts as an inhibitory neurotransmitter, but in all regions of the CNS, it also works as a co-agonist with L-glutamate at N-methyl-D-aspartate receptors (NMDARs). The glycine fluxes in the CNS are regulated by two specific transporters for glycine, GlyT1 and GlyT2, perhaps with the cooperation of diverse neutral amino acid transporters like Asc-1 or SNAT5/SN2. While GlyT2 and Asc-1 are neuronal proteins, GlyT1 and SNAT5 are mainly astrocytic, although neuronal forms of GlyT1 also exist. GlyT1 has attracted considerable interest from the medical community and the pharmaceutical industry since compelling evidence indicates a clear association with the functioning of NMDARs, whose activity is decreased in various psychiatric illnesses. By controlling extracellular glycine, transporter inhibitors might potentiate the activity of NMDARs without activating excitotoxic processes. Physiologically, GlyT1 is a central actor in the cross talk between glutamatergic, glycinergic, dopaminergic, and probably other neurotransmitter systems. Many of these relationships begin to be unraveled by studies performed in recent years using genetic and pharmacological models. These studies are also clarifying the interactions between glycine, glycine transporters, and other co-agonists of the glycine site of NMDARs like D-serine. These findings are also relevant to understand the pathophysiology of devastating diseases like schizophrenia, depression, anxiety, epilepsy, stroke, and chronic pain.

Integrated metabolomics and lipidomics profiling of hippocampus reveal metabolite biomarkers in a rat model of chronic unpredictable mild stress-induced depression

“…Glutamine and GABA might be potential target for further depression diagnosis and antidepressants development. Glycine, a semi-essential amino acid and a basic nutrient, is part of the endogenous antioxidant glutathione, but more importantly, glycine could be involved in oxygen stress and the cell membrane injury processes of depression (31). Phenylalanine, an essential amino acid, is the precursor of catecholamines, which could be as neurotransmitters and adrenalinelike substances that also play crucial roles in depression.…”

Plasma amino acids profile in first-episode psychosis, unaffected siblings and community-based controls

“…We selected the aforementioned amino acids for the following reasons: (i) serine and glycine are co-agonists of N-methyl-d-aspartate receptor (NMDAR) 23,24 ; glutamine is a non-essential amino acid and the precursor of glutamic acid 25 ; proline is a multifunctional amino acid that can modulate the function of glutamic acid decarboxylase 26 and the glutamic acid itself; (ii) regarding the dopaminergic system, we explored the tyrosine amino acid, which is the precursor of dopamine 27 ; (iii) we also investigated the amino acid tryptophan, which is the precursor of serotonin 28 ; and finally (iv) we evaluated the GABAergic system, by measuring the GABA plasma levels.…”

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

“…Glycine is released by Renshaw interneurons and regulates motoneurons' excitability, exerting negative feedback through recurrent inhibition (53). Glycinergic inhibitory interneurons are involved also in the spinal reflex coordination, mediating reciprocal inhibition in stretch reflex circuits and regulating the coordination of opposing muscles (54). The anatomical distribution of glycine immunoreactive (IR) cell bodies points to the cochlear nuclei, the superior olivary complex, the medial nuclei of the trapezoid body, the cerebellar cortex, the deep cerebellar nuclei, the area postrema, and the thalamus of adult rats as main localizations (55,56).…”