Glycine-(and D-Serine)-Related Neurotransmission: Promising Therapeutic Targets with Still Unsolved Problems

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 3862

Special Issue Editor


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Guest Editor
Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Italy Viale Cembrano 4, 16148 Genoa, Italy
Interests: amino acid neurotransmission; neurotransmitter release; glycine; neurotransmitter transporters

Special Issue Information

Dear Colleagues,

The neurotransmitter glycine is involved in several physiological and pathological conditions in the Central Nervous System. This peculiar transmitter exhibits crucial inhibitory but also “excitatory” functions, the latter as a co-agonist of glutamate at the NMDA receptors. Aside from glycine, the D-amino acid D-serine is also a major NMDA co-agonist, exhibiting crucial physiological roles. During the last two decades, advances in the knowledge of glycine release, receptors, transporters and related functions, and the availability of pharmacological modulators have unveiled promising novel therapeutic targets for neurological and/or psychiatric disorders. However, to date, some disappointing outcomes have also been reported as regards translation to a clinical level. This relevant area of neurosciences is being further explored and, hopefully, better results are still to come.

In this Special Issue, it is hoped that original research as well as review articles will help to increase and disseminate knowledge in the field. Finally, studies leading to advances in the basic knowledge of the above-mentioned biological systems are undoubtedly important and their submission is encouraged.

Potential topics include (but are not limited to):

  • Drugs interacting with glycine receptors or transporters and psychiatric disorders (schizophrenia, mood disorders, obsessive-compulsive disorder, addiction, cognitive disorders, etc.).
  • D-serine and related pathological and pharmacological issues.
  • Glycine/D-serine and pathological pain.
  • Glycine/D-serine and neurodegenerative diseases, epilepsy, and startle syndromes, among others.
  • Neurobiology of glycine-related neurotransmission, including interactions with other transmitters.

Dr. Luca Raiteri
Guest Editor

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Keywords

  • glycine
  • d-serine
  • neurotransmission
  • amino acid neurotransmitters
  • glycine transporters
  • glycine transporters inhibitors
  • glycine receptors
  • psychiatric disease
  • pain
  • neurotransmitter release

Published Papers (3 papers)

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Research

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17 pages, 2895 KiB  
Article
The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function
by Lu-Ping Lu, Wei-Hua Chang, Yi-Wen Mao, Min-Chi Cheng, Xiao-Yi Zhuang, Chi-Sheng Kuo, Yi-An Lai, Tsai-Miao Shih, Teh-Ying Chou and Guochuan Emil Tsai
Biomedicines 2024, 12(4), 853; https://doi.org/10.3390/biomedicines12040853 - 12 Apr 2024
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Abstract
It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the [...] Read more.
It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction. Full article
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20 pages, 3370 KiB  
Article
Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals
by Katia Cortese, Maria Cristina Gagliani and Luca Raiteri
Biomedicines 2023, 11(12), 3152; https://doi.org/10.3390/biomedicines11123152 - 27 Nov 2023
Cited by 1 | Viewed by 1365
Abstract
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 [...] Read more.
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. Full article
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Review

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21 pages, 2826 KiB  
Review
Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance
by Anna Rita Galambos, Zsolt Tamás Papp, Imre Boldizsár, Ferenc Zádor, László Köles, Laszlo G. Harsing, Jr. and Mahmoud Al-Khrasani
Biomedicines 2024, 12(2), 421; https://doi.org/10.3390/biomedicines12020421 - 12 Feb 2024
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Abstract
The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the [...] Read more.
The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B receptor remains a future target for the discovery of drugs to restore opioid efficacy. Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation, which ultimately ends with GluN2B receptor overactivation and glutamate release. The presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor activation. The extrasynaptic localization of the GluN2B receptor means it is influenced by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1). Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence of high glutamate levels or unconventional MOR activation on astrocytes could further activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby reducing opioid tolerance. Full article
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