The Duplicated α7 Subunits Assemble and Form Functional Nicotinic Receptors with the Full-length α7

Wang, Ying; Xia, Cheng; Indersmitten, Tim; Freedman, Robert; Leonard, Sherry; Lester, Henry A.

doi:10.1074/jbc.m114.582858

Cited by 70 publications

(112 citation statements)

References 67 publications

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“…Quantitative analyses of the mean fluorescence intensity (MFI) in vector-and CHRFAM7A-transduced cells confirmed the significance of this shift ( Figure 5E). These data suggest that stable CHRFAM7A overexpression either increased BT binding by altering ligand binding of a heteropentameric complex or by regulating CHRNA7 gene expression, thereby facilitating, not inhibiting, α7nAChR transport to the cell surface (3,9,(12)(13)(14).…”

Section: Biological Consequence Of Chrfam7a Gene Expression In Thp1 Cmentioning

confidence: 98%

“…These data support the hypothesis that long-term and stable expression of CHRFAM7A modulates CHRNA7 availability to the surface. Alternatively, the CHRFAM7A protein may form a human-specific α7nAChR heteropentamer at the leukocyte cell surface with modified ligand specificity, tropism and binding kinetics, compared with the α7nAChR homopentamer found in all species (3,9,(12)(13)(14). Among other significantly changed differential genes, versican (#1, 4.5-fold), tensin-like protein (#4, 8.7-fold), SIGLEC1 (#7, 3.6-fold), glipican 6 (#15, 5.1-fold) and EPSTI1 (#18, 3.3-fold) expression all tie to cell adhesion, which itself is a phenotypic difference between stable CHRFAM7A-and GFP-transduced cells ( Figure 5).…”

Section: R E S E a R C H A R T I C L E M O L M E D 2 1 : 3 2 3 -3 3 6mentioning

confidence: 99%

“…More recently, however, its detection in normal human leukocytes (10,11) has gained particular attention because several in vitro studies have shown that CHRFAM7A modifies α7nAChR channel activity and changes ligand tropism (12)(13)(14). Because α7nAChR activation is closely tied to the inflammatory responses of peripheral tissues, these observations raise the possibility that CHRFAM7A may be particularly relevant to gauging inflammation in humans.…”

Section: Introductionmentioning

confidence: 99%

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A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Costantini

Dang

Yurchyshyna

et al. 2015

Mol Med

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The human genome contains a variant form of the α7-nicotinic acetylcholine receptor (α7nAChR) gene that is uniquely human. This CHRFAM7A gene arose during human speciation and recent data suggests that its expression alters ligand tropism of the normally homopentameric human α7-AChR ligand-gated cell surface ion channel that is found on the surface of many different cell types. To understand its possible significance in regulating inflammation in humans, we investigated its expression in normal human leukocytes and leukocyte cell lines, compared CHRFAM7A expression to that of the CHRNA7 gene, mapped its promoter and characterized the effects of stable CHRFAM7A overexpression. We report here that CHRFAM7A is highly expressed in human leukocytes but that the levels of both CHRFAM7A and CHRNA7 mRNAs were independent and varied widely. To this end, mapping of the CHRFAM7A promoter in its 5′-untranslated region (UTR) identified a unique 1-kb sequence that independently regulates CHRFAM7A gene expression. Because overexpression of CHRFAM7A in THP1 cells altered the cell phenotype and modified the expression of genes associated with focal adhesion (for example, FAK, P13K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC) and cancer (kit, kitL, ras, cFos cyclinD1, Frizzled and GPCR), we conclude that CHRFAM7A is biologically active. Most surprisingly however, stable CHRFAM7A overexpression in THP1 cells upregulated CHRNA7, which, in turn, led to increased binding of the specific α7nAChR ligand, bungarotoxin, on the THP1 cell surface. Taken together, these data confirm the close association between CHRFAM7A and CHRNA7 expression, establish a biological consequence to CHRFAM7A expression in human leukocytes and support the possibility that this human-specific gene might contribute to, and/or gauge, a human-specific response to inflammation.

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Section: Biological Consequence Of Chrfam7a Gene Expression In Thp1 Cmentioning

confidence: 98%

Section: R E S E a R C H A R T I C L E M O L M E D 2 1 : 3 2 3 -3 3 6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Costantini

Dang

Yurchyshyna

et al. 2015

Mol Med

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“…First, CHRFAM7A has the capacity to form cell surface heteropolymers with wild-type a7nAChR (61). Second, it is reported to exert a dominant negative effect on a7nAChR and regulate the appearance of a7nAChR on the cell surface.…”

Section: Stdmentioning

confidence: 99%

CHRFAM7A: a human‐specific α7‐nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS

et al. 2015

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The human genome contains a unique, distinct, and human-specific a7-nicotinic acetylcholine receptor (a7nAChR) gene [CHRNA7 (gene-encoding a7-nicotinic acetylcholine receptor)] called CHRFAM7A (gene-encoding dup-a7-nicotinic acetylcholine receptor) on a locus of chromosome 15 associated with mental illness, including schizophrenia. Located 59 upstream from the "wild-type" CHRNA7 gene that is found in other vertebrates, we demonstrate CHRFAM7A expression in a broad range of epithelial cells and sequenced the CHRFAM7A transcript found in normal human fetal small intestine epithelial (FHs) cells to prove its identity. We then compared its expression to CHRNA7 in 11 gut epithelial cell lines, showed that there is a differential response to LPS when compared to CHRNA7, and characterized the CHRFAM7A promoter. We report that both CHRFAM7A and CHRNA7

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“…A partial duplication of CHRNA7 resulting in the chimeric gene CHRFAM7A, which is present only in humans, has been associated with schizophrenia (Sinkus et al, 2009;Neri et al, 2012). Its gene product, dupa7, lacks part of the binding site and may act as a negative modulator of a7 (Wang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

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The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the a7 subunit are unique because of their high Ca 21 permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. The a7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. a7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, a7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit a7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of a7, key pillars for rational drug design.

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The Duplicated α7 Subunits Assemble and Form Functional Nicotinic Receptors with the Full-length α7

Cited by 70 publications

References 67 publications

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

CHRFAM7A: a human‐specific α7‐nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

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