Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA

Egebjerg, Jan; Bettler, Bernhard; Hermans‐Borgmeyer, Irm; Heinemann, Stephen F.

doi:10.1038/351745a0

Cited by 605 publications

(337 citation statements)

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“…Because kainate receptor agonists are excitotoxic, drugs that inhibit kainate receptor desensitization may represent a useful strategy to facilitate kainate receptor function (Egebjerg et al 1991;Wilding and Huettner 1997). This increase in kainate receptor activity may also facilitate NMDA receptor-mediated neurotransmission, and offer yet another approach to the recent augmentation strategies targeting the NMDA receptor in the treatment of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Meador‐Woodruff

2001

Neuropsychopharmacology

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A growing literature suggests glutamatergic dysfunction in schizophrenia. Perhaps the strongest evidence for glutamatergic involvement in this illness is that dissociative anesthetics, especially phencyclidine and ketamine, can cause a schizophreniform psychosis in normal humans, and worsen psychotic symptoms in persons with schizophrenia (Itil et al. 1967;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Luby et al. 1962). These drugs are uncompetitive inhibitors of the NMDA subtype of glutamate receptor, suggesting that schizophrenia may be associated with decreased NMDA receptor activity (Javitt and Zukin 1991;Carlsson and Carlsson 1990). Further, facilitators of NMDA receptor activity have been shown to improve psychotic symptoms. Since direct agonists of this receptor are neurotoxic, other therapeutic strategies have been used to enhance NMDA receptor activity. Agonists at the glycine co-agonist site of the NMDA receptor have been found to improve negative psychotic symptoms, providing additional support for diminished NMDA receptor activity in schizophrenia (Goff et al. 1995;Goff et al. 1999;Heresco-Levy et al. 1999;Javitt et al. 1994).In addition to the NMDA subtype, however, there NO . 5 are additional families of cation-selective ionotropic glutamate receptors, the AMPA and kainate subtypes. Although the NMDA receptor is the subtype of glutamate receptor usually implicated in schizophrenia, the other ionotropic glutamate receptors also may be abnormal in this illness; abnormalities. While a growing literature suggests abnormal expression of both NMDA and AMPA receptors in the brain in schizophrenia (reviewed in Meador-Woodruff and Healy 2000), much less is known about potential abnormalities of the kainate receptor in this illness. The ionotropic glutamate receptors share a common structural motif, and are each composed of four or five family-specific subunits that form ligandgated ion channels (Hollmann and Heinemann 1994). Kainate receptors are composed of the low affinity gluR5, gluR6, and gluR7 subunits, and the high affinity KA1 and KA2 subunits (Hollmann and Heinemann 1994). The gluR5, gluR6, and gluR7 subunits assemble into homomeric complexes, or heteromerically coassemble with KA1 and KA2, resulting in receptors with distinct pharmacological properties, suggesting that subunit composition, at least in part, determines the functional properties of the kainate receptor (Lerma 1998).Only several studies have examined the kainate-associated subunits in schizophrenic brain. Decreased expression of gluR6 and KA2 mRNA were noted in several hippocampal regions, although gluR6 mRNA was not found to be changed in the cerebellum in schizophrenia in this same study (Porter et al. 1997). A recently published study suggested that gluR7 and KA1 subunit transcripts are decreased in the superior frontal gyrus in schizophrenics, similar to decreases also noted by this investigator for some of the subunits associated with the AMPA and NMDA receptors (Sokolov 1998). Only one study to date has examine...

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Section: Discussionmentioning

confidence: 99%

Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Meador‐Woodruff

2001

Neuropsychopharmacology

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“…Alignment of the amino-acid sequence of the molluscan polypeplide with those of three rat glutamate receptor subunits, The sequences o|" GIuRI (AMPA-selective: [3]), GIuRS-2 (one form of GluR5 that is responsive to L-glutamate only; [6]). GIuR6 (KA-selective; [8] other is found in the C-terminal 79 amino acids which occur after TM4, a region that has also been assigned an extracellular location in vertebrates [3,4]. In view of its predicted size, hydropathic profile and strong sequence similarity to vertebrate ionotropic glutamate receptor subunits, we conclude that this polypeptide is a subunit of a molluscan glutamate-gated ion-channel receptor.…”

Section: Resultsmentioning

confidence: 74%

“…In the absence of biochemical data on this invertebrate subunit, it is difficult to draw definite conclusions about the exact number and locations of membrane-spanning domains; however, for simplicity, we assume that the topology of this polypeptide is similar to that proposed for vertebrate glutamate receptor subunits [3,4]. The mature Lymnaean polypeptide displays significant identity to rat [3][4][5][6]8] glutamate receptor subunits (GluRI, 43%: GIuR2, 46%; GIuR3, 45%; GIuR4, 43%; GluR5, 37% and GIuR6, 39%); in particular, it exhibits pronounced similarity to vertebrate sequences around TM3 (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, molecular biological studies have led to the isolation of 6 different vertebrate non-NMDA ionotropic glutamate receptor subunit cDNAs [3][4][5][6][7][8]. When these cDNAs were expressed singly either in Xenopus oocytes [3,[5][6][7][8] or in mammalian cells [4], homo-oligo-meric receptors were formed that were AMPA-selective (GIuRI to GluR4), KA-selective (GIuR6) or responsive to L-glutamate alone (GIuR5).…”

Section: Introductionmentioning

confidence: 99%

“…When these cDNAs were expressed singly either in Xenopus oocytes [3,[5][6][7][8] or in mammalian cells [4], homo-oligo-meric receptors were formed that were AMPA-selective (GIuRI to GluR4), KA-selective (GIuR6) or responsive to L-glutamate alone (GIuR5). No sequence has yet been reported for any invertebrate glutamate receptor.…”

Section: Introductionmentioning

confidence: 99%

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Cloning of a cDNA that encodes an invertebrate glutamate receptor subunit

1991

FEBS Letters

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A full-length eDNA which encodes a putative glutamate receptor polypeptide was isolated from the pond snail Lymnaea stagnalis, using a short stretch of exonic sequence and two variants of the polymerase chain reaction. In this first comparison of invertebrate and vertebrate glutamate receptor sequences, the mature molluscan polypeptide, which comprises 898 amino acids and has a predicted M~ of 100 913, displays between 37% and 46% amino-acid identity to the rat ionotropie glutamate receptor subunits, GIuRI to GIuR6.

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Colocalization of ionotropic glutamate receptor subunits with NADPH-diaphorase-containing neurons in the rat mesopontine tegmentum

Inglis

Semba

1996

J. Comp. Neurol.

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Tegmental cholinergic neurons vary their discharge patterns across the sleep-wake cycle, and glutamate is suggested to play an important role in determining these firing patterns. Cholinergic and noncholinergic neurons in the mesopontine tegmentum have different susceptibilities to various excitotoxins, presumably because of heterogeneity in the expression of glutamate receptor subtypes in this area. By using a double-labeling procedure that combines nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase) histochemistry and avidin-biotin-peroxidase immunocytochemistry with diaminobenzidine as the chromogen, we compared the colocalization of AMPA receptor subunits GluR1, GluR2/3, and GluR4, kainate receptor subunits GluR5/6/7, and an NMDA receptor subunit NMDAR1 on NADPH-diaphorase-positive (cholinergic) neurons in the mesopontine tegmentum. Throughout the brainstem, neurons immunoreactive for GluR2/3 and NMDAR1 were most numerous, whereas neurons labeled for GluR1, GluR4, and GluR5/6/7 were less common. Specifically within the mesopontine tegmentum, the proportion of double-labeled neurons in the diaphorase-containing cell population was highest with GluR1 (43%) and lowest with GluR5/6/7 (12%). Regardless of the receptor subunit type, the greatest numbers of double-labeled neurons were observed in the pedunculopontine tegmental nucleus pars compacta and the fewest in the dorsal aspect of the laterodorsal tegmental nucleus. In addition, there were regional differences in the relative expression of receptor subunits and diaphorase-positive neurons across the subdivisions of the tegmental cholinergic column. Because each ionotropic subunit confers distinctive properties to a receptor channel, the present results suggest that mesopontine cholinergic neurons have nonuniform responses to glutamate and are also discriminable from basal forebrain cholinergic neurons in terms of glutamate receptor configuration.

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Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA

Cited by 605 publications

References 17 publications

Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Cloning of a cDNA that encodes an invertebrate glutamate receptor subunit

Colocalization of ionotropic glutamate receptor subunits with NADPH-diaphorase-containing neurons in the rat mesopontine tegmentum

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