Zinc potentiates agonist-lnduced currents at certain splice variants of the NMDA receptor

Hollmann, Michael; Boulter, Jim; Maron, Cornelia; Beasley, Lora; Sullivan, Jane; Pecht, Gerlinde; Heinemann, Stephen F.

doi:10.1016/0896-6273(93)90209-a

Cited by 589 publications

(394 citation statements)

References 52 publications

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“…Based upon pharmacological experiments with recombinant receptors expressed in Xenopus oocytes, it has been proposed that the presence of the NRl + subunit confers the antagonistpreferring NMDA receptor subtype properties and the NRlsubunit is responsible for agonist-preferring subtype (Hollmann et al, 1993). The anatomical evidence presented in this report suggests that in many brain regions, high-affinity 3H-CPP binding sites are coexpressed with NRl+ mRNA (r = 0.59).…”

Section: Discussionmentioning

confidence: 75%

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The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

et al. 1994

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The relationship between four pharmacologically distinct NMDA receptor subtypes, identified in radioligand binding studies, and the recently identified NMDA receptor subunits (NR1a-g, NR2A-D) has not been determined. In this report, we demonstrate that the anatomical distribution of the four NMDA receptor subtypes strikingly parallels the distribution of mRNA encoding NR2A-D subunits. The distribution of NR2A mRNA was very similar to that of “antagonist-preferring” NMDA receptors [defined by high-affinity 3H-2-carboxypiperazine-4-yl-propyl- 1-phosphonic (3H-CPP) binding sites; correlation coefficient = 0.88]. Agonist-preferring NMDA receptors localized to brain regions expressing both NR2B mRNA and NR1- mRNA (NR1 splice variant lacking insert 1). NR2C mRNA was largely restricted to the cerebellar granule cell layer, a region that displays a unique pharmacological profile. NR2D mRNA localized exclusively to those diencephalic nuclei that have a fourth, distinct pharmacological profile (typified by the midline thalamic nuclei). The pharmacology of native NMDA receptors was compared to that of heteromeric NMDA receptors expressed in Xenopus oocytes (NR1/NR2A, NR1/NR2B, NR1/NR2C). The oocyte-expressed NR1/NR2A receptor displayed a higher affinity for antagonists and a slightly lower affinity for agonists than the NR1/NR2B receptor. These patterns are analogous to those found for radioligand binding to native receptors in the lateral thalamus and medial striatum, respectively. NMDA receptors in the lateral thalamus (with a high density of NR2A subunit mRNA) displayed higher affinity for antagonists and a lower affinity for agonists than did NMDA receptors of the medial striatum (a region rich in NR2B mRNA). Relative to the NR1/NR2A and NR1/NR2B receptors, oocyte-expressed NR1/NR2C receptors had a lower affinity specifically for both D-3-(2- carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene) and homoquinolinate (HQ). This pattern was identical to that observed for cerebellar (NR2C-containing) versus forebrain (NR2A- and NR2B- containing) NMDA receptors. Taken together, the data in this report suggest that the four previously identified native NMDA receptor subtypes differ in their NR2 composition. Furthermore, the NR2 subunits significantly contribute to the anatomical and pharmacological diversity of NMDA receptor subtypes.

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Section: Discussionmentioning

confidence: 75%

“…Alternative splicing of a single NRl gene generates eight isoforms with distinct functional properties (Anantharam et al, 1992;Durand et al, 1992Durand et al, , 1993Sugihara et al, 1992;Hollmann et al, 1993). Heterogeneity within the NR2 subunit family results from expression of four closely related genes Monyer et al, 1992;Ishii et al, 1993).…”

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confidence: 99%

The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

et al. 1994

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“…These results suggest the implication of a genomic mechanism of action in this specific region of the hippocampus. It has to be noted that our evaluation of the NMDA receptor subunit 1 mRNA reflects a pool of eight potential isoforms in all regions studied (Sugihara et al 1992;Hollmann et al 1993). Previous results have also suggested the implication of a classical genomic mechanism of action.…”

Section: Nmda Receptors Mrna Levelsmentioning

confidence: 88%

“…In situ hybridization was performed using previously published sequences of oligonucleotides (Monyer et al 1992) complementary to rat cRNA encoding subunits residues between transmembrane domains I and II, encoding amino acids 566-580 of the mature peptide NMDA receptors subunit 1 (5'-TTCCTCCTCCTCCTCACTGT-TCACCTTGAATCGGCCAAAGGGACT-3'), 567-579 of the NMDA receptors subunit 2A (5'-AGAAGGCCC-GTGGGGAGCTTTCCCTTTGGCTAAGTTTC-3'), and 557-572 of the NMDA receptors subunit 2B (5'-GGG-CCTCCTGGCTCTCTGCCATCGGCTAGGCACCTGTT-GTAACCC-3'); note that the sequence of the oligonucleotide against NMDA receptor subunit 1 mRNA detects a population of eight distinct isoforms of a number of alternative splice variants (Sugihara et al 1992;Hollmann et al 1993). Oligonucleotides were 3' end-labeled with terminal transferase (Boehringer Mannheim) using 20 pmol cDNA and 50 Ci [␣-35 S] dATP (1200-1400 Ci/mmol; NEN).…”

Section: In Situ Hybridization Of Nmda Receptorsmentioning

confidence: 99%

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

Cyr

Thibault

Morissette

et al. 2001

Neuropsychopharmacology

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Hormonal specificity of modulation of N-methyl-D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreasedIt has been shown that the female sex steroid estradiol exerts profound effects on neuronal differentiation during development (Toran-Allerand et al. 1983) and recently, accumulating evidence support also a modulatory role of estrogens in the normal maintenance of brain function during aging (Simpkins et al. 1994). Beneficial effects of estradiol in mood disorders (i.e., depression, pre-menstrual syndrome, post-natal depression), as well as mental diseases, such as schizophrenia and Gille de la Tourette's syndrome, have been reported (Di Paolo 1994;Fink et al. 1998). Moreover, a beneficial role of estradiol in neurodegenerative disFrom the Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, (CHUL), and Faculty of Pharmacy, Laval University, Sainte-Foy, Quebec, Canada, G1V 4G2.Address correspondence to: Dr. Thérèse Di Paolo, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, CHUQ, 2705, Laurier Boulevard, Sainte-Foy, Quebec, Canada G1V 4G2.Received July 5, 2000; revised December 20, 2000; accepted January 3, 2001. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 2 SERMs Modulate NMDA Receptors 243 eases, such as Alzheimer has been recently suggested (Tang et al. 1996;Henderson 1997;Inestrosa et al. 1998). However, the mechanisms by which these effects of estrogens are yet to be fully characterized. N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptor, have been implicated, as mediators, in some effects of estradiol on morphological plasticity and related physiological and cognitive processes in the brain (Moriyoshi et al. 1991). However, only few studies have directly investigated the role of estradiol in regulating NMDA receptors in rat and, in addition, these studies have focused on the effects of estradiol on hippocampal NMDA receptors (Woolley and McEwen 1992;Gazzaley et al. 1996;Woolley et al. 1997). We have recently investigated the effects of estradiol on the NMDA receptors agonist sites in brain regions implicated in mental disorders, such as frontal cortex, striatum, and nucleus accumbens (Cyr et al. 2000a). Our experiments showed that ovariectomy, as well as estradiol have regional specific effects since, for example, ovariectomy decreases NMDA receptor specific binding in hippocampal CA1 and dentate gyrus regions, whereas it has no effect in frontal cortex. In contrast, estradiol increases NMDA specific binding in the hippocampal CA1 and the dentate gyrus, but it decreases this binding in the frontal cortex (Cyr et al. 2000a).The present study sought to determine whether changes observed previously at the protein level after hormonal withdrawal due to ovariectomy or after estradiol treatment reflect changes at the level of gene transcription...

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“…Functional NMDARs are comprised of several types of subunits, viz., an obligatory NR1 subunit, of which there are eight splice variants (1a/b-4 a/b) (Hollmann et al, 1993;Zukin and Bennett, 1995), and one or more regulatory NR2 (A-D) subunits (Molinoff et al, 1994) and/or NR3 subunits (Das et al, 1998;Chatterton et al, 2002;Madry et al, 2007).NR subunits are expressed temporally and regionally in the central nervous system and the nature of the subunit associations in the functional NMDAR control the properties of this receptor (Paoletti and Neyton, 2007;Prorok and Castellino, 2007). Some functions of apoE have been linked to those of the NMDAR.…”

Section: Introductionmentioning

confidence: 99%

N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

et al. 2008

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The effects of a synthetic apoE1 peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor-binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, has been investigated. The activity of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was found to depend on the low density lipoprotein receptor-related protein (LRP). Competition experiments with receptor associated protein (RAP) and activated α 2 macroglobulin (α 2 M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and α 2 M*. A co-receptor of LRP, cell-surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was 3-fold greater for NMDAR-transfected wild-type Chinese Hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR-inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

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Zinc potentiates agonist-lnduced currents at certain splice variants of the NMDA receptor

Cited by 589 publications

References 52 publications

The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

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