Subunit specificity and mechanism of action of NMDA partial agonist d-cycloserine

Sheinin, Anton; Shavit, Sara; Benveniste, Morris

doi:10.1016/s0028-3908(01)00073-9

Cited by 116 publications

(110 citation statements)

References 21 publications

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“…This effect is accompanied by higher affinity at NR1/2C receptors -NR1/2C > NR1/2D >> NR1/ 2B > NR1/2A 395 . In contrast, similar data showed that the intrinsic activity at NR1/2C was even higher (192%) 396 . Therefore, it is likely that the biphasic effects seen in vivo are due to agonistic actions at NR1/2C receptors at lower doses and inhibition of NR1/2A and NR1/2B containing receptors at higher doses.…”

Section: Dose-responsementioning

confidence: 74%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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Section: Dose-responsementioning

confidence: 74%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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“…Cyclic and halogenated analogs of glycine, including D-cycloserine, act as GluN1 partial agonists (Hood et al, 1989;Priestley and Kemp, 1994;Sheinin et al, 2001;Dravid et al, 2010) (Table 7). Although D-cycloserine is a partial agonist of GluN2A-, GluN2B-, and GluN2D-containing NMDA receptors, the responses of GluN2C-containing NMDA receptors are greater in D-cycloserine than those evoked by glycine (Sheinin et al, 2001;Dravid et al, 2010).…”

Section: B N-methyl-d-aspartate Receptor Agonistsmentioning

confidence: 99%

“…Although D-cycloserine is a partial agonist of GluN2A-, GluN2B-, and GluN2D-containing NMDA receptors, the responses of GluN2C-containing NMDA receptors are greater in D-cycloserine than those evoked by glycine (Sheinin et al, 2001;Dravid et al, 2010). This raises the possibility that potentiation of GluN2C-containing NMDA receptors could underlie the positive effects of D-cycloserine on cognition, fear extinction, and motor dysfunction (Kalia et al, 2008;Norberg et al, 2008) through action on GluN2C-expressing neurons .…”

Section: B N-methyl-d-aspartate Receptor Agonistsmentioning

confidence: 99%

“…This compound is a partial agonist at the glycine site and may preferentially activate NMDA receptors containing the GluN2C subunit (Sheinin et al, 2001;Dravid et al, 2010) expressed on interneurons and cerebellar granule cells . Initial clinical studies of D-cycloserine indicated a beneficial effect on negative symptoms over a narrow dose range (Goff et al, 1999).…”

Section: F N-methyl-d-aspartate Receptor Potentiationmentioning

confidence: 99%

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Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…D-Cycloserine (DCS), an antibiotic treatment used for tuberculosis, acts as a partial agonist relative to glycine at GluN1/GluN2A, GluN1/GluN2B, and GluN1/GluN2D receptors. By contrast, a maximally effective concentration of DCS produces more current at GluN1/GluN2C receptors than the endogenous agonist glycine, leading to selective enhancement of GluN1/GluN2C receptors when DCS replaces glycine at the GluN1 agonist binding site (Sheinin et al, 2001;Dravid et al, 2010). NMDAR hypofunction has been suggested to underlie some aspects of schizophrenia (Krystal et al, 1994;Olney et al, 1999;Lisman, 2012), and DCS has shown positive results in schizophrenic patients, suggesting increased occupancy of the agonist binding site on GluN1 and thereby enhancement NMDAR function (Goff et al, 1995;Goff et al, 2008;Gottlieb et al, 2011).…”

Section: Introductionmentioning

confidence: 97%

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

et al. 2014

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NMDA receptors are tetrameric complexes of GluN1, GluN2A-D, and GluN3A-B subunits and are involved in normal brain function and neurologic disorders. We identified a novel class of stereoselective pyrrolidinone (PYD) positive allosteric modulators for GluN2C-containing NMDA receptors, exemplified by methyl 4-(3-acetyl-4-hydroxy-1-[2-(2-methyl-1H-indol-3-yl)ethyl]-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate. Here we explore the site and mechanism of action of a prototypical analog, PYD-106, which at 30 mM does not alter responses of NMDA receptors containing GluN2A, GluN2B, and GluN2D and has no effect on AMPA [a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] and kainate receptors. Coapplication of 50 mM PYD-106 with a maximally effective concentration of glutamate and glycine increases the response of GluN1/GluN2C NMDA receptors in HEK-293 cells to 221% of that obtained in the absence of PYD (taken as 100%). Evaluation of the concentration dependence of this enhancement revealed an EC 50 value for PYD of 13 mM. PYD-106 increased opening frequency and open time of single channel currents activated by maximally effective concentrations of agonist but only had modest effects on glutamate and glycine EC 50 . PYD-106 selectively enhanced the responses of diheteromeric GluN1/GluN2C receptors but not triheteromeric GluN1/GluN2A/GluN2C receptors. Inclusion of residues encoded by GluN1-exon 5 attenuated the effects of PYD. Three GluN2C residues (Arg194, Ser470, Lys470), at which mutagenesis virtually eliminated PYD function, line a cavity at the interface of the ligand binding and the amino terminal domains in a homology model of GluN1/GluN2C built from crystallographic data on GluN1/GluN2B. We propose that this domain interface constitutes a new allosteric modulatory site on the NMDA receptor.

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Subunit specificity and mechanism of action of NMDA partial agonist d-cycloserine

Cited by 116 publications

References 21 publications

A Review of Glutamate Receptors I: Current Understanding of Their Biology

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

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