Background: Synapse formation and function is modulated by intrinsic and extrinsic non-autonomous factors.Results: Astrocytes induce synapse formation through TGF-β1 pathway. TGF-β1 synaptogenic property is dependent on d-serine signaling.Conclusion: TGF-β induces excitatory glutamatergic synapses in vertebrates.Significance: This is a novel molecular mechanism that might impact synaptic function and shed light on new potential therapeutic targets for synaptic deficit diseases.
D-Serine is a D-amino acid that occurs at high levels in the mammalian brain and is an endogenous ligand of the "glycine site" of N-methyl D-aspartate (NMDA) 1 receptors (1-4). NMDA receptors play key roles in excitatory synaptic transmission, plasticity, and learning and memory (5). Overactivation of the NMDA receptor and the resultant influx of calcium into cells is a major culprit in the cell death that occurs following stroke and neurodegenerative diseases. Blockers of the "glycine site" of the receptor are neuroprotective in animal models of stroke (5). Endogenous D-serine is required for NMDA receptor activation, and its removal markedly decreases NMDA receptor activity (3). In the vertebrate retina, endogenous D-serine may also mediate the light-dependent increase in neuronal activity by activating NMDA receptors (6). More recently, D-serine was suggested to play a role in the long term potentiation of synaptic transmission in the hippocampus, indicating a role of endogenous D-serine in long term synaptic plasticity (7).D-Serine is synthesized by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme enriched in the mammalian brain (8, 9). Serine racemase has high sequence homology with the fold-type II group of PLP enzymes, such as serine/threonine dehydratase and D-serine dehydratase (10, 11). In addition to converting L-to D-serine, serine racemase catalyzes the ␣,-elimination of water from L-serine to form pyruvate and ammonia (12). The initial rates of racemization and ␣,-elimination of L-serine by serine racemase are strongly stimulated by magnesium and ATP, indicating that the complex Mg⅐ATP is a physiological ligand of the enzyme (12).In accordance with accepted mechanisms of PLP-catalyzed reactions (13-16), a mechanism for racemization and ␣,-elimination catalyzed by serine racemase is depicted in Scheme 1. PLP, bound to the enzyme through an internal aldimine with The termination of signaling by a neurotransmitter in the brain normally requires its re-uptake and metabolism. D-Serine signaling is thought to involve its release from cells to
High levels of D-serine occur in the brain, challenging the notion that D-amino acids would not be present or play a role in mammals. D-serine levels in the brain are even higher than many L-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. D-serine is synthesized by a serine racemase (SR) enzyme, which directly converts L-to D-serine. We now report that SR is a bifunctional enzyme, producing both D-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of D-serine and augmented release of pyruvate to culture media. We identified substances present in HEK 293 and astrocyte cell extracts that strongly stimulate D-serine production by SR and elicit production of pyruvate. Experiments with recombinant enzyme reveal that Mg 2؉ and ATP present in the cell extracts are physiological cofactors and increase 5-to 10-fold the rates of racemization and production of pyruvate. As much as three molecules of pyruvate are synthesized for each molecule of D-serine produced by SR. This finding constitutes a previously undescribed mechanism underlying D-amino acid synthesis in mammals, different from classical amino acid racemases present in bacteria. Our data link the production of D-serine to the energy metabolism, with implications for the metabolic and transmitter crosstalk between glia and neurons.glutamate receptors ͉ pyruvate ͉ astrocytes I n recent years, it has been shown that astrocytes and neurons exhibit a dynamic bidirectional signaling that profoundly influences neuronal activity and development (1). Astrocytes modulate synaptic transmission by releasing chemical transmitters and eliciting Ca 2ϩ waves in nearby neurons. The search for new transmitter molecules in the brain uncovered the presence of high levels of D-serine in astrocytes, a D-amino acid not previously thought to occur in mammals (2, 3). D-serine is synthesized by a glial-enriched enzyme serine racemase (SR), which directly converts L-to D-serine (4-7). SR does not bear significant homology with bacterial racemases, and little is known about the mechanism and regulation of D-serine production.D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3,8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically (8). Massive stimulation of NMDA receptors is implicated in neural damage after stroke (9), and inhibitors of SR may be useful to prevent stroke damage. Thus, inhibitors of SR provide a strategy to decrease NMDA receptor coactivation and may be useful in conditions in which overstimulation of NMDA receptors plays a pathological role.To clarify the role of D-serine as a modulator of NMDA receptors, one should identify the factors that regulate SR and D-serine signaling. In this paper, we explored mechanisms regulating the production of D-serine by SR. We demonstrate that SR is a unique bifunctional enzyme, produ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.