Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells

Silver, Ian A.; Deas, Judith; Erecińska, Maria

doi:10.1016/s0306-4522(96)00600-8

Cited by 181 publications

(134 citation statements)

References 58 publications

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“…This fits with conflicting, generally minimal effects reported of nNOS deletion on NMDA transmission (18). SR is uniquely stimulated by ATP, which appears to be absolutely required for enzyme activity and to display high affinity for SR with a K m of Ϸ12 M, far lower than endogenous ATP levels in most cells (19). This activation of SR is independent of ATP hydrolysis being elicited by nonmetabolized ATP analogs (5).…”

Section: Discussionsupporting

confidence: 72%

Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation

Mustafa

Kumar

Selvakumar

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

124

102

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Serine racemase (SR) generates D-serine, a coagonist with glutamate at NMDA receptors. We show that SR is physiologically S-nitrosylated leading to marked inhibition of enzyme activity. Inhibition involves interactions with the cofactor ATP reflecting juxtaposition of the ATP-binding site and cysteine-113 (C113), the site for physiological S-nitrosylation. NMDA receptor physiologically enhances SR S-nitrosylation by activating neuronal nitricoxide synthase (nNOS) . These findings support a model whereby postsynaptic stimulation of nitric-oxide (NO) formation feeds back to presynaptic cells to S-nitrosylate SR and decrease D-serine availability to postsynaptic NMDA receptors.neuronal nitric-oxide synthase ͉ NMDA receptor ͉ S-nitrosylation G lutamate neurotransmission through NMDA receptors requires a coagonist originally thought to be glycine. Recent studies indicate that in most portions of the brain, D-serine is the physiological coagonist because selective degradation of D-serine but not glycine markedly reduces NMDA transmission (1, 2), whereas retraction of D-serine-producing glia in the hypothalamus of lactating rats also diminishes NMDA transmission (2). D-serine is formed from L-serine by serine racemase (SR), which, like D-serine, is selectively enriched in glia (2, 3), although recent studies indicate some neuronal localization (4). SR, a pyridoxal phosphate-requiring enzyme, also displays an absolute requirement for ATP, which is not hydrolyzed during SR activation (5). SR binds the glutamate receptor interacting protein, which also binds to AMPA subtypes of glutamate receptors with glutamate receptor interacting protein markedly activating SR and providing a means whereby glutamate stimulation of SR-containing cells augments D-serine formation (6).In postsynaptic cells, NMDA signaling is mediated in part by neuronal nitric-oxide synthase (nNOS) because calcium entering through NMDA receptor channels binds to calmodulin associated with nNOS (7,8). Extensive studies have documented a feedback from postsynaptic to presynaptic glutamatergic nerve terminals, which modulates NMDA neurotransmission, especially in long-term potentiation (9). Nitric oxide (NO) may be a retrograde messenger of long-term potentiation (10-12), although the area is controversial (12). Because SR is a component of the NMDA synaptic complex, we wondered whether it is influenced by NO. In the present study, we demonstrate that SR is physiologically S-nitrosylated leading to inhibition of enzyme activity mediated by interactions with ATP. NMDA transmission stimulates SR S-nitrosylation suggesting a feedback mechanism to diminish presynaptic formation of D-serine. ResultsWe demonstrated S-nitrosylation of SR in multiple ways. Incubation of the NO donor S-nitroso-glutathione (GSNO) with SR in vitro leads to robust nitrosylation (Fig. 1A). In HEK293 cells, treatment with the NO donor sodium nitroprusside also provides S-nitrosylation (Fig. 1B). NO produced by nNOS S-nitrosylates SR, as is evident in HEK293 cells transfected with nNOS (Fi...

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Section: Discussionsupporting

confidence: 72%

Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation

Mustafa

Kumar

Selvakumar

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

124

102

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“…Mg 2ϩ and ATP activate SR at concentrations much below those found in the cytosol, which are about 0.6 and 3-6 mM, respectively (16,22). The content of ATP in normal cellular extracts (Ϸ250 M) is in large excess to that needed to activate SR, explaining our observation that a 10-fold dilution does not affect their stimulatory activity.…”

Section: Discussionmentioning

confidence: 50%

“…4C). Although apyrase enzyme also degrades ADP, the lower levels of intracellular ADP (16) and the much lower affinity of SR to ADP indicate that ADP is not likely to physiologically regulate SR.…”

Section: Resultsmentioning

confidence: 99%

Cofactors of serine racemase that physiologically stimulate the synthesis of the N -methyl- d -aspartate (NMDA) receptor coagonist d -serine

Miranda

Panizzutti

Foltyn

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

198

183

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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...

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“…Cellular insults such as hypoxia-ischemia decrease not only cellular ATP levels but also induce anaerobic glycolysis that produces a pronounced lactic acidosis followed by H ϩ extrusion and external acidification. In turn, this leads to excess accumulation of Na i ϩ (via the Na ϩ /H ϩ exchanger) and Ca 2ϩ i (via the Na ϩ /Ca 2ϩ exchanger acting in reverse mode) (72)(73)(74), which if sufficiently severe, can lead to neuronal and glial cell death (9,(75)(76)(77)(78). Hippocampal pyramidal neurons are especially susceptible to damage from hypoxic-ischemic episodes (79 -82).…”

Section: Discussionmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase Regulates Hippocampal Neuronal pH by Recruiting Na+/H+ Exchanger NHE5 to the Cell Surface

Jinadasa

Szabó

Numata

et al. 2014

Journal of Biological Chemistry

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Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells

Cited by 181 publications

References 58 publications

Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation

Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation

Cofactors of serine racemase that physiologically stimulate the synthesis of the N -methyl- d -aspartate (NMDA) receptor coagonist d -serine

Activation of AMP-activated Protein Kinase Regulates Hippocampal Neuronal pH by Recruiting Na+/H+ Exchanger NHE5 to the Cell Surface

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