The pharmacological specificity of N‐methyl‐<scp>d</scp>‐aspartate receptors in rat cerebral cortex: correspondence between radioligand binding and electrophysiological measurements

Grimwood, Sarah; Foster, Alan C.; Kemp, John A.

doi:10.1111/j.1476-5381.1991.tb09799.x

Cited by 26 publications

(10 citation statements)

References 39 publications

(43 reference statements)

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“…In addition, glycine also inhibited the binding in all areas. The effect was antagonized by the glycine antagonist, 7-CKA, in all regions, indicating that the possibility of negative allosteric modulation of [3H]-CGP 39653 binding, through the activation of the associated strychnine-insensitive glycine site of the NMDA receptor channel complex (Mugnaini et al, 1993) (Lynch et al, 1993;Marti et al, 1993;Laurie & Seeburg, 1994 (Buller et al, 1994) strictly paralleled that of the mRNA encoding for the NR2A subunit (Laurie & Seeburg, 1994 CPP and CGS 19755 which were more in accord with the low affinity site (Fagg et al, 1990;Grimwood et al, 1991 (Monaghan et al, 1988;Buller et al, 1994). It may be noteworthy that in our data, because of the different allosteric modulation, basal [3H]-CGP 39653 binding was already partially inhibited by the endogenous glycine to a greater extent in striatum with respect to the cerebral cortex and the thalamus.…”

Section: Discussionmentioning

confidence: 95%

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain

Mugnaini¹,

Amsterdam²,

Ratti³

et al. 1996

British J Pharmacology

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Binding of D,L-(E)-2-amino-4-[3H]-propyl-5-phosphono-3-pentenoic acid ([3H]showed that the inhibition was lower in striatum (72% of control), with respect to cortex (66% of control) and hippocampal formation (58% of control).6 The inhibitory action of 10 gM glycine was reversed by 100 gM 7-chloro-kynurenic acid (7-CKA), a competitive antagonist of the glycine site of the NMDA receptor channel complex, in all areas tested. Moreover, reversal by 7-CKA was not the same in all regions (P<0.05, two-ways ANOVA). In fact, in the presence of 10 gM glycine and 100 gM 7-KCA, specific [3H]-CGP 39653 binding in the striatum was 131% of control, which was significantly greater (Fisher's protected LSD) than binding in the hippocampus and the thalamus (104% and 112% of control, respectively).7 These results demonstrate that [3H]-CGP 39653 binding can be inhibited by glycine in rat brain regions containing NMDA receptors; moreover, they suggest the existence of regionally distinct NMDA receptor subtypes with a different allosteric mechanism of [3H]-CGP 39653 binding modulation through the associated glycine site.

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Section: Discussionmentioning

confidence: 95%

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain

Mugnaini¹,

Amsterdam²,

Ratti³

et al. 1996

British J Pharmacology

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“…Measurements of the KD Of L-glutamate binding to purified membranes have led to values ranging from 120 to 620 nm (see Grimwood, Foster & Kemp, 1991). This is in the range expected if the NMDA receptor in purified membranes is in a state comparable to that it adopts in 'stabilized' outside-out patches, in which the KD of binding would reflect predominantly binding to the desensitized states.…”

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confidence: 98%

Activation and desensitization of N‐methyl‐D‐aspartate receptors in nucleated outside‐out patches from mouse neurones.

Sather

Dieudonné

MacDonald

et al. 1992

The Journal of Physiology

224

188

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SUMMARY1. Activation and desensitization of N-methyl-D-aspartate (NMDA) receptors were studied in large outside-out patches excised from cultured embryonic neurones dissociated from mouse forebrain. The patches were exposed to rapid changes of NMDA or L-glutamate concentrations in the presence of glycine at concentrations (10-20 ,UM) saturating the modulatory site of the NMDA receptor.2. Immediately after formation of the patch the responses to NMDA and Lglutamate showed a slow and small desensitization, even with high concentrations of agonist. During the following hour, the peak response either decreased or remained relatively stable, but in all cases the desensitization increased and accelerated until it stabilized. In this 'stabilized' state, the desensitization produced by high concentrations of NMDA (1 mM) or L-glutamate (300 /tM) had an exponential time course, with a time constant of about 30 ms. The ratio of the peak over the steadystate current was in the order of 40 for NMDA and about 30 for L-glutamate.3. Concentration-response curves were built for the peak and the plateau responses, for NMDA and for L-glutamate. The comparison of these curves indicated that (i) the EC50 of the peak (Kapp) was always higher than the EC50 of the plateau (KSS); (ii) the two EC50 values for NMDA (Kapp and KSS) were higher than those for L-glutamate; (iii) the Hill coefficient was close to 1X4 for each of the four curves.4. The application of NMDA or L-glutamate at a low concentration for 3 s periods reduced the response to a subsequent application of the same agonist at a saturating concentration. The IC50 of this 'predesensitization', termed Kpre, was lower than the EC50 of the steady-state response, KS.5. The onset rates of desensitization increased with the concentration of agonist.The EC50 of this relation was close to the value of Kapp. W. SATHER AND OTHERS well described by the sum of two exponentials both of which were faster for NMDA than for L-glutamate.7. The recovery from desensitization after a long (3 s) pulse of agonist was approximately exponential, with a time constant of about 0 5 s for NMDA and about 3-5 s for L-glutamate.8. The results can be interpreted by using a model similar to those used for the nicotinic receptor assuming that (i) the NMDA receptor exists, in the absence of agonist, in both an activatable (R) and two desensitized (D) states; (ii) the R and D states have two equivalent binding sites for NMDA agonists; (iii) the affinity of the R state for the agonist is lower than that of the D states. However, in contrast with the hypotheses made for the nicotinic receptor, it is not possible to assume that the reactions leading to the opening of the channel through activation of the R states are much faster than the reactions connecting the R and D states.9. The differences between L-glutamate and NMDA responses suggest that Lglutamate differs from NMDA by a higher affinity for the various receptor states as well as by a higher efficacy.10. The evolution of the NMDA receptor behaviour between ...

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“…*p i 0.05 for difference from control. tabolism in this system, the concentrations of the antagonists used in these experiments should have blocked their corresponding receptors by over 90% (Pearce et al, 1985;Honor6 et al, 1988;Ivins and Molinoff, 1990;Grimwood et al, 1991). Although high levels of PI hydrolysis were stimulated by D -A s~ in the current studies, previous studies in adult rats suggested that D-As~ does not stimulate PI metabolism (Nicoletti et al, 1986b).…”

Section: Resultsmentioning

confidence: 99%

Multiple Subtypes of Excitatory Amino Acid Receptors Coupled to the Hydrolysis of Phosphoinositides in Rat Brain

Littman

Glatt

Robinson

1993

Journal of Neurochemistry

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The excitatory amino acid (EAA) analogues quisqualate, ibotenate, and trans‐(±)‐1‐amino‐1, 3‐cyclopentanedicarboxylate (trans‐ACPD) activate the metabotropic EAA receptors that are coupled to the hydrolysis of Phosphoinositides (PI). Previous studies of hippocampal cross sections demonstrated that PI hydrolysis stimulated by these agonists can be inhibited by either L‐aspartate‐β‐ hydroxamate (L‐AβHA) or DL‐2‐amino‐3‐phosphonopropionate (DL‐AP3). The goal of the present studies was to determine if all metabotropic EAA receptors are sensitive to L‐AβHA and DL‐AP3. Two approaches were used. In the first, using cerebellar cross sections, the effects of these agonists and inhibitors were examined. The EC50 values (the concentrations required to evoke half‐maximal stimulation) of quisqualate, ibotenate, and trans‐ACPD in cerebellum were similar to the EC50 values that we observed previously in hippocampus, but neither L‐AβHA nor DL‐ AP3 blocked PI hydrolysis. The EC50 values were 0.65 ± 0.17 μM for quisqualate, 12.8 ± 2.5 μM for ibotenate, and 18.1 ± 3.1 μM for trans‐ACPD. All data were best fit to theoretical curves that had Hill slopes of 1. In the second approach, another EAA analogue, D‐aspartate, was identified as an agonist that stimulates PI hydrolysis. The EC50for PI hydrolysis stimulated by D‐aspartate was 470 ± 90 μM in hippocampus. Neither L‐AβSHA nor DL‐AP3 blocked PI hydrolysis stimulated by D‐aspartate in hippocampus. Furthermore, antagonists of ionotropic EAA receptors, antagonists of other receptor systems coupled to PI hydrolysis, and inhibitors of the Na+‐dependent L‐glutamate transport process also did not block PI hydrolysis stimulated by D‐aspartate. These data support the presence of three pharmacologically distinct metabotropic EAA receptor subtypes.

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The pharmacological specificity of N‐methyl‐d‐aspartate receptors in rat cerebral cortex: correspondence between radioligand binding and electrophysiological measurements

Abstract: 1 The pharmacological specificity of N-methyl-D-aspartate (NMDA)

Cited by 26 publications

References 39 publications

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain

Activation and desensitization of N‐methyl‐D‐aspartate receptors in nucleated outside‐out patches from mouse neurones.

Multiple Subtypes of Excitatory Amino Acid Receptors Coupled to the Hydrolysis of Phosphoinositides in Rat Brain

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The pharmacological specificity of N‐methyl‐d‐aspartate receptors in rat cerebral cortex: correspondence between radioligand binding and electrophysiological measurements

Abstract: 1 The pharmacological specificity of N-methyl-D-aspartate (NMDA)

Cited by 26 publications

References 39 publications

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [3H]‐CGP 39653 in rat brain

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [3H]‐CGP 39653 in rat brain

Activation and desensitization of N‐methyl‐D‐aspartate receptors in nucleated outside‐out patches from mouse neurones.

Multiple Subtypes of Excitatory Amino Acid Receptors Coupled to the Hydrolysis of Phosphoinositides in Rat Brain

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Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain

Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [³H]‐CGP 39653 in rat brain