Comparative pharmacology of the human NMDA-receptor subtypes R1-2A, R1-2B, R1-2C and R1-2D using an inducible expression system

Feuerbach, Dominik; Loetscher, Erika; Neurdin, Stephanie; Koller, Manuel

doi:10.1016/j.ejphar.2010.04.002

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…In other words, there is an apparent lack of data from human NMDA receptors. Relatively few studies have described functional properties of heterologously expressed human NMDA receptors (Bednar et al, 2004; Claiborne et al, 2003; Curtis et al, 2003; Daggett et al, 1998; Feuerbach et al, 2010; Grimwood et al, 1996a; Grimwood et al, 1996b; Hess et al, 1996; Hess et al, 1998; Le Bourdelles et al, 1994; Priestley et al, 1996; Priestley et al, 1995; Steinmetz et al, 2002; Steinmetz et al, 2004; Usala et al, 2003; Varney et al, 1996; Wafford et al, 1995). Although the amino acid sequence is highly conserved between rat and human subunits, some variation exist that may nonetheless confer significant pharmacological and functional differences.…”

Section: Introductionmentioning

confidence: 99%

“…A number agonists and competitive antagonists have been characterized on human recombinant NMDA receptor subtypes using electrophysiological methods and fluorescence-based measurements of intracellular Ca 2+ (Bednar et al, 2004; Daggett et al, 1998; Feuerbach et al, 2010; Hess et al, 1996; Hess et al, 1998; Le Bourdelles et al, 1994; Priestley et al, 1995; Varney et al, 1996; Wafford et al, 1995). The GluN2B-selective non-competitive antagonist ifenprodil has also been evaluated on human NMDA receptors with some variation in the obtained IC 50 -values, ranging from 110 nM to 2.2 µM at human GluN1/GluN2B (Bednar et al, 2004; Feuerbach et al, 2010; Hess et al, 1998; Varney et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…The GluN2B-selective non-competitive antagonist ifenprodil has also been evaluated on human NMDA receptors with some variation in the obtained IC 50 -values, ranging from 110 nM to 2.2 µM at human GluN1/GluN2B (Bednar et al, 2004; Feuerbach et al, 2010; Hess et al, 1998; Varney et al, 1996). No studies have provided IC 50 values at human NMDA receptors for un-competitive antagonist (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Molecular pharmacology of human NMDA receptors

Hedegaard

Hansen

Andersen

et al. 2012

Neurochemistry International

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N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular pharmacology of human NMDA receptors

Hedegaard

Hansen

Andersen

et al. 2012

Neurochemistry International

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“…Thus, there seems to be an overall good correlation between the pharmacological data obtained at recombinant human and rat NMDA receptors when tested in voltage-clamp experiments in Xenopus oocytes. On the other hand, potencies obtained in our electrophysiological recordings are considerably higher when compared to the values of the same compounds tested in Ca 2+ flux experiments (Feuerbach et al 2010) at recombinant human NMDA receptors expressed in mammalian cell lines, highlighting the utility of comparing different readouts for pharmacological characterization.…”

Section: Discussionmentioning

confidence: 95%

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Heusler

Tourette

Cussac

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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N-methyl-D-aspartate (NMDA) receptor channels are implicated in a wide range of physiological and pathophysiological processes, and a large number of pharmacological agents have been introduced that target the receptor via diverse mechanisms of action. Amongst others, subunit selectivity (in particular for the NR2B receptor subunit) and rapid unblocking kinetics have been put forward as favourable pharmacological properties of NMDA receptor-targeting drugs. Here, we describe a pharmacological characterization of human recombinant NMDA receptors expressed in Xenopus oocytes in an electrophysiological set-up. Using this approach, we compare inhibitor potencies of several known NMDA receptor ligands as well as unblocking kinetic properties of selected compounds. All compounds tested had similar potencies at receptors containing NR2A or NR2B receptors with the exception of traxoprodil, which was selective for NR2B. The rank order of potency was (+)MK-801 > phencyclidine (PCP) ≈ traxoprodil > memantine ≈ ketamine > duloxetine. In line with its proposed rapid dissociation properties, the relatively well-tolerated drug memantine exhibits markedly faster unblocking than ketamine and PCP, similar to the low-affinity compound, duloxetine. Electrophysiological recording in Xenopus oocytes thus allows a relatively convenient comparison of key pharmacological parameters at recombinant human NMDA receptors.

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“…tetracycline induced expression. However, even in such systems, due to the high expression levels after induction, the presence of functional receptors is highly toxic, requiring cell cultures to be maintained in the presence of potent channel blockers such as Ketamine 14 , 15 . However, these channel blockers are hard to wash-out and toxic to the cells resulting in cell death and release of glycine and glutamate, which occupy the ligand binding sites and occlude the pharmacological modulation of receptor activity.…”

Section: Introductionmentioning

confidence: 99%

A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine

Guo¹,

Camargo²,

Yeboah³

et al. 2017

Sci Rep

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N-methyl-D-aspartate-receptors (NMDARs) are ionotropic glutamate receptors that function in synaptic transmission, plasticity and cognition. Malfunction of NMDARs has been implicated in a variety of nervous system disorders, making them attractive therapeutic targets. Overexpression of functional NMDAR in non-neuronal cells results in cell death by excitotoxicity, hindering the development of cell-based assays for NMDAR drug discovery. Here we report a plate-based, high-throughput approach to study NMDAR function. Our assay enables the functional study of NMDARs with different subunit composition after activation by glycine/D-serine or glutamate and hence presents the first plate-based, high throughput assay that allows for the measurement of NMDAR function in glycine/D-serine and/or glutamate sensitive modes. This allows to investigate the effect of small molecule modulators on the activation of NMDARs at different concentrations or combinations of the co-ligands. The reported assay system faithfully replicates the pharmacology of the receptor in response to known agonists, antagonists, positive and negative allosteric modulators, as well as the receptor’s sensitivity to magnesium and zinc. We believe that the ability to study the biology of NMDARs rapidly and in large scale screens will enable the identification of novel therapeutics whose discovery has otherwise been hindered by the limitations of existing cell based approaches.

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Comparative pharmacology of the human NMDA-receptor subtypes R1-2A, R1-2B, R1-2C and R1-2D using an inducible expression system

Cited by 6 publications

References 23 publications

Molecular pharmacology of human NMDA receptors

Molecular pharmacology of human NMDA receptors

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine

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