Human GluR6c, a functional splicing variants of GluR6, is mainly expressed in non-nervous cells

Barbon, Alessandro; Gervasoni, Annalisa; LaVia, Luca; Orlandi, Cesare; Jaskolski, Frédéric; Perrais, David; Barlati, Sergio

doi:10.1016/j.neulet.2008.01.049

Cited by 6 publications

(10 citation statements)

References 24 publications

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“…Among the five variants, GluR6A is specifically expressed in brain cells, while B, C, D and E variants of GluR6 were abundantly transcribed in the fibroblasts. While variants A, B and C have been previously described ([Barbon et al, 2001] and [Barbon et al, 2008]), we have demonstrated GluR6D and GluR6E as two additional novel variants expressed in non-neuronal cells. All five variants share an identical N-terminus, but they have distinct C-termini of varying lengths.…”

Section: Discussionsupporting

confidence: 46%

“…The variants B, C, D and E were specific for human fibroblast cells. It warrants mention that GluR6 variants A and B have been previously described [Barbon et al, 2001] and variant C was published [Barbon et al, 2008] while this manuscript was in preparation. There are no reports of any other variants of GluR6 in the literature.…”

Section: Resultsmentioning

confidence: 99%

“…The various members of the iGluR family have been cloned ([Myers et al, 1999] and [Dingledine et al, 1999]) and the promoter sequences from some ionotropic receptors have also been characterized ([Myers et al, 1999],[Bai and Kusaik, 1995], [Sasner and Buonanno, 1996], [Suchanek et al, 1995], [Borges and Dingledine, 1998], [Kohler et al, 1994], [Myers et al, 1998] and [Huang and Gallo, 1997]). The genomic organization of GluR6 and expression patterns of its A, B and C splice variants in neuronal tissues and non-neuronal cell lines have already been described ([Barbon et al, 2001] and [Barbon et al, 2008]). Among these three variants, GluR6A was the main isoform expressed in the central nervous system, while barely detectable levels of GluR6B and extremely low levels of GluR6C were present in spinal cord and corpus callosum.…”

Section: Introductionmentioning

confidence: 99%

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Novel spliced variants of ionotropic glutamate receptor GluR6 in normal human fibroblast and brain cells are transcribed by tissue specific promoters

Zhawar

Deriel

Kaur

et al. 2010

Gene

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The members of the ionotropic glutamate receptor family, namely, a-amino-3-hydroxy-S-methyl-4-isoxazole propionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors, are important mediators of the rapid synaptic transmission in the central nervous system. We have investigated the splicing pattern and expression of the kainate receptor subunit GluR6 in human fibroblast cell lines and brain tissue. We demonstrate the expression of GluR6A variant specifically in brain, and four variants, namely, GluR6B, GluR6C, GluR6D and GluR6E in fibroblast cell lines. The variants GluR6D and GluR6E have not been described before, and appear to be specific for non-neuronal cells. Genomic analysis and cloning of the sequence preceding the transcribed region led to the identification of two tissue specific promoters designated as neuronal promoter PN and non-neuronal promoter PNN. We have used RNA ligase mediated RACE and in silico analyses to locate two sets of transcription start sites, and confirmed specific transcripts initiated by PN and PNN in brain cells and fibroblasts, respectively. The domain structure of variants GluR6D and GluR6E revealed the absence of three transmembrane domains. The lack of these domains suggests that the mature receptors arising from these variant subunits may not function as active channels. Based on these structural features in GluR6D and GluR6E, and the observations that GluR6B, GluR6C, GluR6D and GluR6E are exclusively expressed in non-neuronal cells, it is likely that these receptor subunits function as non-channel signaling proteins.

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Section: Discussionsupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel spliced variants of ionotropic glutamate receptor GluR6 in normal human fibroblast and brain cells are transcribed by tissue specific promoters

Zhawar

Deriel

Kaur

et al. 2010

Gene

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“…In other words, hGluK2a is the only isoform that contains both M867 in its 908 amino acid residues (10) and this trafficking motif. Not surprisingly, hGluK2a is found to be the only isoform capable of efficiently trafficking to the plasma membrane (38). It is therefore conceivable that the location of M867 based on its close proximity to the trafficking motif positions this residue for its role in facilitating receptor trafficking.…”

Section: Discussionmentioning

confidence: 99%

Channel-Opening Kinetic Mechanism for Human Wild-Type GluK2 and the M867I Mutant Kainate Receptor

et al. 2010

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GluK2 is a kainate receptor subunit that is alternatively spliced at the C-terminus. Previous studies implicated GluK2 in autism. In particular, the methionine-to-isoleucine replacement at amino acid residue 867 (M867I) that can only occur in the longest isoform of the human GluK2 (hGluK2), as the disease (autism) mutation, is thought to cause gain-of-function. However, the kinetic properties of the wild-type hGluK2 and the functional consequence of this gain-of-function mutation at the molecular level are not well understood. To investigate whether the M867I mutation affects the channel properties of the human GluK2 kainate receptor, we have systematically characterized the rate and the equilibrium constants pertinent to channel opening and channel desensitization for this mutant and the wild-type hGluK2 receptor, along with the wild-type rat GluK2 kainate receptor (rGluK2) as the control. Our results show that the M867I mutation does not affect either the rate or the equilibrium constants of the channel opening but does slow down the channel desensitization rate by ~1.6-fold at saturating glutamate concentrations. It is possible that a consequence of this mutation on the desensitization rate is linked to facilitating the receptor trafficking and membrane expression, given the close proximity of M867 to the forward trafficking motif in the C-terminal sequence. By comparing the data of the wild-type human and rat GluK2 receptors, we also find that the human GluK2 has a ~3-fold smaller channel-opening rate constant but an identical channel-closing rate constant, and thus a channel-opening probability of 0.85 vs. 0.96 for rGluK2. Furthermore, the intrinsic equilibrium dissociation constant K 1 for hGluK2, like the EC 50 value, is ~2-fold lower than rGluK2. Our results therefore suggest that the human GluK2 is relatively a slowly activating channel but more sensitive to glutamate, as compared to the rat ortholog, despite the fact that the human and rat forms share 99% sequence homology.GluK2 (previously known as GluR6) is a subunit of the glutamate ion channel receptor family of kainate subtype (1-3). Within this family, glutamate ion channel receptors are subdivided by their prototypical agonists into N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptors, and kainate receptors (3). Within the kainate receptor subtype, there are five subunits, i.e., GluK1-5. GluK2, like GluK1 and 3, can form functional, homomeric channels, whereas GluK4-5 can only form † This work was supported in part by grants from the National Institutes of Health (R01 NS060812), Department of Defense (W81XWH-04-1-0106), and the Muscular Dystrophy Association. * To whom correspondence should be addressed. ; lniu@albany.edu. SUPPORTING INFORMATION AVAILABLEThe supporting information includes a figure showing Hill equation fit to the dose-response relationship, and a table showing the results of the nonlinear regression data for the best fit of n, K 1 and k op to the observed rate constan...

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“…mRNA expression analysis has demonstrated that the human GluK2c splice variant in brain is mainly expressed in nonneuronal cells and barely expressed in neurons [61]. GluK2 can operate not only in an inotropic, but also in a metabotropic mode [62].…”

Section: Effects Of Ssrismentioning

confidence: 99%

Signal Transduction in Astrocytes during Chronic or Acute Treatment with Drugs (SSRIs, Antibipolar Drugs, GABA-ergic Drugs, and Benzodiazepines) Ameliorating Mood Disorders

Hertz

Song

et al. 2014

Journal of Signal Transduction

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Chronic treatment with fluoxetine or other so-called serotonin-specific reuptake inhibitor antidepressants (SSRIs) or with a lithium salt “lithium”, carbamazepine, or valproic acid, the three classical antibipolar drugs, exerts a multitude of effects on astrocytes, which in turn modulate astrocyte-neuronal interactions and brain function. In the case of the SSRIs, they are to a large extent due to 5-HT2B-mediated upregulation and editing of genes. These alterations induce alteration in effects of cPLA2, GluK2, and the 5-HT2B receptor, probably including increases in both glucose metabolism and glycogen turnover, which in combination have therapeutic effect on major depression. The ability of increased levels of extracellular K+ to increase [Ca2+]i is increased as a sign of increased K+-induced excitability in astrocytes. Acute anxiolytic drug treatment with benzodiazepines or GABAA receptor stimulation has similar glycogenolysis-enhancing effects. The antibipolar drugs induce intracellular alkalinization in astrocytes with lithium acting on one acid extruder and carbamazepine and valproic acid on a different acid extruder. They inhibit K+-induced and transmitter-induced increase of astrocytic [Ca2+]i and thereby probably excitability. In several cases, they exert different changes in gene expression than SSRIs, determined both in cultured astrocytes and in freshly isolated astrocytes from drug-treated animals.

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Human GluR6c, a functional splicing variants of GluR6, is mainly expressed in non-nervous cells

Cited by 6 publications

References 24 publications

Novel spliced variants of ionotropic glutamate receptor GluR6 in normal human fibroblast and brain cells are transcribed by tissue specific promoters

Novel spliced variants of ionotropic glutamate receptor GluR6 in normal human fibroblast and brain cells are transcribed by tissue specific promoters

Channel-Opening Kinetic Mechanism for Human Wild-Type GluK2 and the M867I Mutant Kainate Receptor

Signal Transduction in Astrocytes during Chronic or Acute Treatment with Drugs (SSRIs, Antibipolar Drugs, GABA-ergic Drugs, and Benzodiazepines) Ameliorating Mood Disorders

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