Functional crosstalk of the glycine transporter GlyT1 and NMDA receptors

Piniella, Dolores; Zafra, Francisco

doi:10.1016/j.neuropharm.2023.109514

Cited by 13 publications

(9 citation statements)

References 223 publications

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“…This process ensures that glutamate concentrations rise briefly, up to 1 mM, for only half a second and then drop back to nanomolar levels ( Andersen and Schousboe, 2023 ; Dienel et al, 2023 ; Purushotham and Buskila, 2023 ). If high glutamate concentrations in the synaptic cleft persisted, the glutamatergic receptors on different parts of the cell, such as the dendritic spines and dendrites itself, would be tonic-activated ( Nimgampalle et al, 2023 ; Orlando et al, 2023 ; Piniella and Zafra, 2023 ). The fast and efficient clearance of glutamate from the extracellular space following neuronal activity is, therefore, necessary for the spatial and temporal limitation of neuronal activation ( Haj-Yasein et al, 2015 ; Lia et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model

Ankul,

Chandran,

Anuragh

et al. 2023

Front. Pharmacol.

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This systematic review analyzes monosodium glutamate (MSG) in the Alzheimer’s disease-like condition to enhance translational research. Our review seeks to understand how MSG affects the brain and causes degenerative disorders. Due to significant preclinical data linking glutamate toxicity to Alzheimer’s disease and the lack of a comprehensive review or meta-analysis, we initiated a study on MSG’s potential link. We searched PubMed, ScienceDirect, ProQuest, DOAJ, and Scopus for animal research and English language papers without time constraints. This study used the PRISMA-P framework and PICO technique to collect population, intervention or exposure, comparison, and result data. It was registered in PROSPERO as CRD42022371502. MSG affected mice’s exploratory behaviors and short-term working memory. The brain, hippocampus, and cerebellar tissue demonstrated neuronal injury-related histological and histomorphometric changes. A total of 70% of MSG-treated mice had poor nesting behavior. The treated mice also had more hyperphosphorylated tau protein in their cortical and hippocampus neurons. Glutamate and glutamine levels in the brain increased with MSG, and dose-dependent mixed horizontal locomotor, grooming, and anxiety responses reduced. MSG treatment significantly decreased phospho-CREB protein levels, supporting the idea that neurons were harmed, despite the increased CREB mRNA expression. High MSG doses drastically lower brain tissue and serum serotonin levels. In conclusion, MSG showed AD-like pathology, neuronal atrophy, and short-term memory impairment. Further research with a longer time span and deeper behavioral characterization is needed.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42022371502].

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Section: Discussionmentioning

confidence: 99%

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model

Ankul,

Chandran,

Anuragh

et al. 2023

Front. Pharmacol.

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“…Accordingly, we propose that NMDA receptors are not involved here as initial targets of the effect of Gly. An involvement of other transport systems that are reported to vehicle Gly with a high affinity (see [9,67]) might be possible, although this further point is not within the aims of the study.…”

Section: Localization and Functions Of Glyts On Hippocampal Glutamate...mentioning

confidence: 99%

“…In the CNS, the two most relevant high-affinity transporters for Gly are known, namely, GlyT1 and GlyT2. GlyT1, originally considered almost exclusively as "glial" transporters, are also present in neurons, particularly in glutamatergic neurons, in areas including the hippocampus [6,7,9,28,29,68,69]. If the presence of GlyT1 in glutamatergic neurons has been well demonstrated, the functional data suggesting that GlyT2 transporters exist in some Glu-releasing nerve terminals in the hippocampus seem very unusual and deserve some comments.…”

Section: Considerations On the Glyt Types Found On Mouse Hippocampal ...mentioning

confidence: 99%

“…Glycine (Gly) is a major inhibitory neurotransmitter (NT) in the mammalian central nervous system (CNS), and it also plays pivotal roles in excitatory neurotransmission as a coagonist of Glutamate (Glu) at the ionotropic NMDA receptor [1]. Interactions between the two amino acid NTs, Gly and Glu, are of particular pathophysiological interest and are the object of many studies (see [2][3][4][5][6][7][8][9] and references therein).…”

Section: Introduction 1transporter-mediated Interactions Between Glyc...mentioning

confidence: 99%

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Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals

Cortese,

Gagliani,

Raiteri

2023

Biomedicines

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Evidence supports the pathophysiological relevance of crosstalk between the neurotransmitters Glycine and Glutamate and their close interactions; some reports even support the possibility of Glycine–Glutamate cotransmission in central nervous system (CNS) areas, including the hippocampus. Functional studies with isolated nerve terminals (synaptosomes) permit us to study transporter-mediated interactions between neurotransmitters that lead to the regulation of transmitter release. Our main aims here were: (i) to investigate release-regulating, transporter-mediated interactions between Glycine and Glutamate in hippocampal nerve terminals and (ii) to determine the coexistence of transporters for Glycine and Glutamate in these terminals. Purified synaptosomes, analyzed at the ultrastructural level via electron microscopy, were used as the experimental model. Mouse hippocampal synaptosomes were prelabeled with [3H]D-Aspartate or [3H]Glycine; the release of radiolabeled tracers was monitored with the superfusion technique. The main findings were that (i) exogenous Glycine stimulated [3H]D-Aspartate release, partly by activation of GlyT1 and in part, unusually, through GlyT2 transporters and that (ii) D-Aspartate stimulated [3H]glycine release by a process that was sensitive to Glutamate transporter blockers. Based on the features of the experimental model used, it is suggested that functional transporters for Glutamate and Glycine coexist in a small subset of hippocampal nerve terminals, a condition that may also be compatible with cotransmission; glycinergic and glutamatergic transporters exhibit different functions and mediate interactions between the neurotransmitters. It is hoped that increased information on Glutamate–Glycine interactions in different areas, including the hippocampus, will contribute to a better knowledge of drugs acting at “glycinergic” targets, currently under study in relation with different CNS pathologies.

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“…In the CNS, GlyT1 is primarily found in fine astrocytic processes and subset of glutamatergic terminals (Zafra et al, 1995; Cubelos et al, 2005), and plays a crucial role in maintaining ambient glycine levels below saturation for NMDARs (Smith et al, 1992; Attwell and Bouvier, 1992; Supplisson and Bergman, 1997; Bergeron et al, 1998; Supplisson and Roux, 2002; Zafra et al, 2017; Piniella and Zafra, 2023). Its main function, however, is to recapture glycine released at inhibitory synapses in the spinal cord, brainstem, cerebellum and retina (Zafra et al, 1995; Gomeza et al, 2003; Eulenburg et al, 2018; Eulenburg and Hülsmann, 2022).…”

Section: Introductionmentioning

confidence: 99%

Dynamic role of GlyT1 as glycine sink or source: pharmacological implications for the gain control of NMDA receptors

Supplisson

2024

Preprint

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Glycine transporter 1 (GlyT1) mediates termination of inhibitory glycinergic receptors signaling in the spinal cord and brainstem, and is also diffusely present in the forebrain. Here, it regulates the ambient glycine concentration influencing the "glycine"-site occupancy of N-methyl-D-aspartate (NMDARs). GlyT1 is a reversible transporter with a substantial, but not excessive, sodium-motive force for uphill transport. This study examines its potential role as a glycine source, either by reversed-uptake or by heteroexchange. I explored how glycine accumulation triggers its release, facilitating the activation of NMDARs by glutamate applied alone. Indeed, glutamate evokes no current in "naive" oocytes coexpressing GluN1/GluN2A and GlyT1, a previously characterized cellular model, but now using GlyT1 as the only potential source of coagonist for NMDAR activation. After glycine uptake, however, glutamate evokes large currents, blocked by ALX-5407 and potentiated by sarcosine, a specific inhibitor and substrate of GlyT1, respectively. These results suggest higher occupancy of the co-agonist site when GlyT1 functions as a glycine source either by reversed-uptake or by heteroexchange. A difference between these two glycine-release mechanisms occurs at hyperpolarized potentials, which induce an apparent voltage-dependent block of NMDAR currents, whereas heteroexchange preserves NMDAR activation at these potentials. Together, these results confirm GlyT1-mediated efflux as a positive regulator of NMDAR co-agonist site occupancy, and demonstrate sarcosine heteroexchange effectiveness in enhancing coagonist site occupancy. Depending on its actual mode of transport, GlyT1-inhibitors and sarcosine may have distinct effects on ambient glycine and NMDAR facilitation, and be a source of variation in reversing NMDAR hypofunction in schizophrenia.

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Functional crosstalk of the glycine transporter GlyT1 and NMDA receptors

Cited by 13 publications

References 223 publications

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model

Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals

Dynamic role of GlyT1 as glycine sink or source: pharmacological implications for the gain control of NMDA receptors

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