Phosphorylation of mouse serine racemase regulates <scp>d</scp>‐serine synthesis

Foltyn, Veronika N.; Zehl, Martin; Dikopoltsev, Elena; Jensen, Ole N.; Wolosker, Herman

doi:10.1016/j.febslet.2010.05.022

Cited by 36 publications

(23 citation statements)

References 10 publications

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“…It has been shown that protein kinase C (PKC)-mediated phosphorylation of SR on serine residues decreases D-Ser levels in astrocytes and neuronal cultures [33]. Phosphorylation of SR on Thr227, which correlates with its translocation from the cytosol to the plasma membrane, also results in lower synthesis of D-Ser [34, 35]. In our study, MLA treatment of 1321N1 cells elicited PKC activation as evidenced by the increase in MARCKS phosphorylation (Fig.…”

Section: Discussionsupporting

confidence: 54%

“…In particular, the preferential affinity of synaptic NMDARs for D-Ser [2, 35] and the presynaptic expression of nAChRs, particularly α7-nAChRs [37, 38, 39], suggest that nAChR inhibitors, especially selective α7-nAChR antagonists, may be useful in the treatment of CNS pathologies associated with NMDA-induced neurotoxicity. The potential therapeutic utility of competitive nAChR antagonists has been previously suggested [40] and the data from this study suggest that non-competitive inhibitors may also be useful.…”

Section: Discussionmentioning

confidence: 99%

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Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells

Singh

Paul

Ramamoorthy

et al. 2013

Cellular Signalling

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Western blot analysis demonstrated that PC-12 cells express monomeric and dimeric forms of serine racemase (m-SR, d-SR) and that 1321N1 cells express m-SR. Quantitative RT-PCR and functional studies demonstrated that PC-12 cells express homomeric and heteromeric forms of nicotinic acetylcholine receptors (nAChR) while 1321N1 cell primarily express the α7-nAChR subtype. The effect of nAChR agonists and antagonists on SR activity and expression was examined by following concentration-dependent changes in intracellular D-Ser levels and SR protein expression. Incubation with (S)-nicotine increased D-Ser levels, which was attenuated by the α7-nAChR antagonist methyllycaconitine (MLA). Treatment of PC-12 cells with mecamylamine (MEC) produced a bimodal reduction of D-Ser reflecting MEC inhibition of homomeric and heteromeric nAChRs, while a unimodal curve was observed with 1321N1 cells, reflecting predominant expression of α7-nAChR. The nAChR subtype selectivity was probed using α7-nAChR selective inhibitors MLA and (R,S)-dehydronorketamine and α3β4-nAChR specific inhibitor AT-1001. The compounds reduced D-Ser in PC-12 cells, but only MLA and (R,S)-dehydronorketamine were effective in 1321N1 cells. Incubation of PC-12 and 1321N1 cells with (S)-nicotine, MEC and AT-1001 did not affect m-SR or d-SR expression, while MLA and (R,S)-dehydronorketamine increased m-SR expression but not SR mRNA levels. Treatment with cycloheximide indicated that increased m-SR was due to de novo protein synthesis associated with phospho-active forms of ERK1/2, MARCKS, Akt and rapamycin-sensitive mTOR. This effect was attenuated by treatment with the pharmacological inhibitors U0126, LY294002 and rapamycin, which selectively block the activation of ERK1/2, Akt and mTOR, respectively, and siRNAs directed against ERK1/2, Akt and mTOR. We propose that nAChR-associated changes in Ca2+ flux affect SR activity, but not expression, and that MLA and (R,S)-dehydronorketamine bind to allosteric sites on the α7-nAChR and promote multiple signaling cascades that converge at mTOR to increase m-SR levels.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells

Singh

Paul

Ramamoorthy

et al. 2013

Cellular Signalling

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“…The N-terminal of serine racemase contains residues that bind to Golga 3, which results in inhibition of ubiqitin-proteosomal serine racemase degradation. In addition to the binding to above proteins, serine racemase can also be activated by phosphorylation [35], whereas S-nitrosylation [36] or membrane binding [37,38] inhibits racemase activity. More detailed information on the regulation of serine racemase can be found in a review article by Baumgart and Rodriguez-Crespo [39].…”

Section: Serine Racemase (Ec 51118)mentioning

confidence: 99%

d-Amino acid metabolism in mammals: Biosynthesis, degradation and analytical aspects of the metabolic study

Ohide

Miyoshi

Maruyama

et al. 2011

Journal of Chromatography B

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“…2B) (25)(26)(27). The enzyme is reported to be post-translationally modified by phosphorylation (28), palmitoylation (29), and nitrosylation (30). SR levels can be modulated by ubiquitin tagging for proteasomal degradation (31).…”

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confidence: 99%

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for β-elimination function

Nelson¹,

Applegate²,

Beio

et al. 2017

Journal of Biological Chemistry

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There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist d-serine. Reported correlation of d-serine levels with disorders including Alzheimer's disease, ALS, and ischemic brain damage (elevated d-serine) and schizophrenia (reduced d-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser, the putative -face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of l-serine over the normally preferred l-serine--sulfate (∼1200-fold change in / ratios) and l (l-THA; ∼5000-fold change in / ratios) alternative substrates. On the other hand, the S84T (which performs l-Ser racemization activity), S84A (good but high for l-THA elimination), and S84N mutants (nearly WT efficiency for l-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with l--β-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with = 31 ± 1.5 μm and 1.5 ± 0.1 mm, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the l-THA and l-serine--sulfate substrates and the l--β-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for l-THA-like β-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser-HO-Lys hydrogen-bonding network in human serine racemase lowers the p of the Ser-face base.

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Phosphorylation of mouse serine racemase regulates d‐serine synthesis

Cited by 36 publications

References 10 publications

Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells

Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells

d-Amino acid metabolism in mammals: Biosynthesis, degradation and analytical aspects of the metabolic study

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for β-elimination function

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