On the transcriptional regulation of neuronal nAChR genes

Matter, Jean‐Marc; Matter-Sadzinski, Lidia; Roztocil, Tomas; Hernandez, M D; Couturier, Sabine; Ong, Ming-Thong; Ballivet, Marc

doi:10.1016/s0928-4257(98)80027-2

Cited by 6 publications

(4 citation statements)

References 19 publications

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“…Sp1 and Sp3 interact with each other and other factors to control expression of the rat ␤4 gene (44,45). Sp1, AP2, and GC-rich sites were present in the chick ␣7 promoter, but the role of these sequences was not defined (35,39). The 5Ј-end of the human ␣7 nAChR gene has also been cloned, and potential Sp1, AP-2, Egr-1, and cAMP response element-binding protein transcription factor binding sites were present, although the role of any of these sequences in regulation of the human ␣7 has not been determined (34).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Rat Neuronal Nicotinic Acetylcholine Receptor α7 Promoter

Nagavarapu

Danthi

Boyd³

2001

Journal of Biological Chemistry

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Neuronal nicotinic acetylcholine receptors (nAChRs) containing the ␣7 subunit are expressed in the central nervous system, autonomic nervous system, retina, adrenal medulla, and PC12 cells. ␣7 nAChRs have been implicated in several important biological activities apart from synaptic transmission such as mediating neurite growth and presynaptic control of neurotransmitter release. A 178-base pair promoter was sufficient to drive high level expression of the ␣7 gene in PC12 cells. The ␣7 promoter was also cell-specific, expressing in PC12 cells but not in L6 rat muscle cells. Within our minimal rat ␣7 nAChR promoter we identified two sequences important for basal level expression. Mutation of a GC-rich sequence at ؊172 relative to the translational start site led to an increase in activity of the promoter, indicating the presence of a negative regulatory element. Upstream stimulatory factor-1 acted to regulate ␣7 expression positively by binding to an E-box at ؊116. A site directly adjacent to the upstream stimulatory factor-1 binding site was shown to bind Egr-1. Sp1 and Sp3 binding also occurred downstream from or overlapping the Egr-1 binding site in the rat ␣7 promoter. Several transcription factors interact in close proximity to control expression of the rat ␣7 nicotinic receptor gene. Neuronal nicotinic acetylcholine receptors (nAChRs)1 mediate synaptic transmission in many parts of the vertebrate central nervous system, as well as in autonomic ganglia, retina, and adrenal medulla. Neuronal nAChRs are pentameric structures (1, 2) that function as ligand-gated ion channels and are composed of multiple ␣ and ␤ subunits. Nine neuronal nAChR ␣ subunit genes (␣2-␣10) and three nAChR ␤ subunit genes (␤2-␤4) have been identified (3-16).One specific subtype of neuronal nAChR is sensitive to ␣-bungarotoxin and composed of ␣7 subunits. ␣7 nAChRs possess several characteristics that set them apart from most nAChRs. ␣7 nAChRs have a high level of Ca 2ϩ permeability, similar to that of the N-methyl-D-aspartate subtype of glutamate receptors (17). ␣7 nAChRs also rapidly desensitize and are expressed both extrasynaptically (or perisynaptically) on neuronal soma and at presynaptic nerve terminals (17, 18).␣7-containing or ␣-bungarotoxin nAChRs have been implicated in several important biological activities apart from synaptic transmission; (i) neurite outgrowth (19 -22), (ii) mediating cell growth (23), (iii) neuronal development and cell death (24 -26), and (iv) presynaptic control of neurotransmitter release (27). Given all of the above functions of ␣7 nAChRs, it is clear that precise mechanisms function to control the time and place of ␣7 gene expression. Because ␣7 nAChRs are most likely homo-oligomeric receptors (at least some of them), regulation of ␣7 gene expression controls the location and timing of ␣7 nAChR functions. To examine the mechanisms that control expression of the ␣7 gene, we have isolated a rat nAChR ␣7 subunit promoter and identified DNA sequences and transcription factors important in regulation of t...

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Section: Discussionmentioning

confidence: 99%

Characterization of a Rat Neuronal Nicotinic Acetylcholine Receptor α7 Promoter

Nagavarapu

Danthi

Boyd³

2001

Journal of Biological Chemistry

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“…A precise regulation of neurotransmitter receptor number is of crucial importance for determining the functional characteristics of the postsynaptic membrane. So far, the transcriptional control of ionotropic receptor genes in the nervous system has been investigated for genes encoding nicotinic acetylcholine receptor [1][2][3], GABA A (γ-aminobutyric acid) receptor [4][5][6] and various glutamate receptor subunits (reviewed in [7]). These studies have shown that the respective promoters share several characteristics, including the lack of TATA and CAAT boxes and multiple transcriptional start sites within CpG-rich genomic regions.…”

Section: Introductionmentioning

confidence: 99%

Exonic Sp1 sites are required for neural-specific expression of the glycine receptor β subunit gene

et al. 2001

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The gene encoding the beta subunit of the inhibitory glycine receptor (GlyR) is widely expressed throughout the mammalian central nervous system. To unravel the elements regulating its transcription, we isolated its 5' non-coding and upstream flanking regions from mouse. Sequence analysis revealed significant differences between the 5' region of the beta subunit gene and the corresponding regions of the homologous GlyR alpha subunit genes; it also identified a novel exon (exon 0) that encodes most of the 5'-untranslated portion of the GlyR beta mRNA. Primer extension experiments disclosed multiple transcriptional start sites. Transfection experiments with luciferase reporter gene constructs showed that sequences encompassing 1.58 kb of upstream flanking region and 180 bp of exon 0 displayed high promoter activity in two neuroblastoma cell lines but not in non-neural cells. Analysis of various deletion constructs showed that the 5' flanking region preceding the transcriptional start sites silences expression in non-neural cells but is not essential for general promoter activity. In contrast, the deletion of sequences within exon 0 drastically decreased or abolished transcription; the removal of sequences harbouring Sp1 consensus sequences within exon 0 decreased expression specifically in a neuroblastoma cell line. Band-shift assays confirmed the binding of Sp1 to sites within the deleted sequence. Our results indicate that neural-specific expression of the GlyR beta subunit gene might depend on a direct interaction of Sp1 transcription factors with cis elements located downstream from transcription initiation sites.

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“…A significant effort has been put forth to elucidate transcriptional mechanisms controlling expression of the nACh receptor genes (40,41). We and others have focused on the regulation of a genomic cluster of receptor genes, those encoding the ␣3, ␣5, and ␤4 subunits (42).…”

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confidence: 99%

Transcriptional Repression by a Conserved Intronic Sequence in the Nicotinic Receptor α3 Subunit Gene

Medel

Gardner

2007

Journal of Biological Chemistry

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The genes encoding the nicotinic acetylcholine receptor ␣3, ␣5, and ␤4 subunits are genomically clustered. These genes are co-expressed in a variety of cells in the peripheral and central nervous systems. Their gene products assemble in a number of stoichiometries to generate several nicotinic receptor subtypes that have distinct pharmacological and physiological properties. Signaling through these receptors is critical for a variety of fundamental biological processes. Despite their importance, the transcriptional mechanisms underlying their coordinated expression remain to be completely elucidated. By using a bioinformatics approach, we identified a highly conserved intronic sequence within the fifth intron of the ␣3 subunit gene. Reporter gene analysis demonstrated that this sequence, termed "␣3 intron 5," inhibits the transcriptional activities of the ␣3 and ␤4 subunit gene promoters. This repressive activity is position-and orientation-independent. Importantly, repression occurs in a cell type-specific manner, being present in cells that do not express the receptor genes or expresses them at very low levels. Electrophoretic mobility shift assays demonstrate that nuclear proteins specifically interact with ␣3 intron 5 at two distinct sites. We propose that this intronic repressor element is important for the restricted expression patterns of the nicotinic receptor ␣3 and ␤4 subunit genes.Neuronal differentiation is a consequence of extrinsic and intrinsic regulatory cascades that ultimately act to regulate, both positively and negatively, gene expression. This process yields mature neurons that express a limited set of genes encoding proteins that perform specific functions (1-9). Part of this repertoire of genes is that of encoding proteins required for neuronal signaling, including neurotransmitter biosynthetic enzymes and their cognate neurotransmitter receptors. Acetylcholine is an excitatory neurotransmitter that interacts with both ionotropic and G-protein-coupled receptors. Signaling through ionotropic nicotinic acetylcholine (nACh) 2 receptors is involved in a variety of behaviors ranging from muscle contraction to memory formation (10 -13). In addition, acetylcholine and its receptors play important roles in neural development (14 -17). Not surprisingly, compromised signaling through nACh receptors is implicated in a number of neurological disorders (18 -35). Thus, understanding the molecular details underlying nACh receptor expression will shed light on various aspects of neural development and function as well as contribute to our understanding of several neuropathological conditions.In the nervous system, nACh receptors are encoded by a conserved family of genes consisting of at least 12 members, ␣2-␣10 and ␤2-␤4 (10, 11, 36 -39). A significant effort has been put forth to elucidate transcriptional mechanisms controlling expression of the nACh receptor genes (40, 41). We and others have focused on the regulation of a genomic cluster of receptor genes, those encoding the ␣3, ␣5, and ␤4 subunits (4...

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On the transcriptional regulation of neuronal nAChR genes

Cited by 6 publications

References 19 publications

Characterization of a Rat Neuronal Nicotinic Acetylcholine Receptor α7 Promoter

Characterization of a Rat Neuronal Nicotinic Acetylcholine Receptor α7 Promoter

Exonic Sp1 sites are required for neural-specific expression of the glycine receptor β subunit gene

Transcriptional Repression by a Conserved Intronic Sequence in the Nicotinic Receptor α3 Subunit Gene

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