Differentiating nicotine- versus schizophrenia-associated decreases of the α7 nicotinic acetylcholine receptor transcript, CHRFAM7A, in peripheral blood lymphocytes

Severance, Emily G.; Dickerson, Faith; Stallings, Cassie; Origoni, Andrea; Sullens, Anne; Monson, Eric; Yolken, Robert H.

doi:10.1007/s00702-008-0164-y

Cited by 14 publications

(14 citation statements)

References 46 publications

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“…Additionally, our findings that nicotine markedly reduces the expression levels of dup␣7 mRNA in MØ (Fig. 7C) are in complete agreement with recent in vivo results showing a lower ␣7 transcript expression in PBMC from smokers than from nonsmokers (57). Further experiments are needed to learn whether cerebral dup␣7 mRNA expression can be regulated by different stimuli, as occurs in MØ.…”

Section: Discussionsupporting

confidence: 80%

Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene

Lucas-Cerrillo¹,

Maldifassi²,

Arnalich

et al. 2011

Journal of Biological Chemistry

115

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The neuronal ␣7 nicotinic receptor subunit gene (CHRNA7) is partially duplicated in the human genome forming a hybrid gene (CHRFAM7A) with the novel FAM7A gene. The hybrid gene transcript, dup␣7, has been identified in brain, immune cells, and the HL-60 cell line, although its translation and function are still unknown. In this study, dup␣7 cDNA has been cloned and expressed in GH4C1 cells and Xenopus oocytes to study the pattern and functional role of the expressed protein. Our results reveal that dup␣7 transcript was natively translated in HL-60 cells and heterologously expressed in GH4C1 cells and oocytes. Injection of dup␣7 mRNA into oocytes failed to generate functional receptors, but when co-injected with ␣7 mRNA at ␣7/dup␣7 ratios of 5:1, 2:1, 1:1, 1:5, and 1:10, it reduced the nicotine-elicited ␣7 current generated in control oocytes (␣7 alone) by 26, 53, 75, 93, and 94%, respectively. This effect is mainly due to a reduction in the number of functional ␣7 receptors reaching the oocyte membrane, as deduced from ␣-bungarotoxin binding and fluorescent confocal assays. Two additional findings open the possibility that the dominant negative effect of dup␣7 on ␣7 receptor activity observed in vitro could be extrapolated to in vivo situations. (i) Compared with ␣7 mRNA, basal dup␣7 mRNA levels are substantial in human cerebral cortex and higher in macrophages.(ii) dup␣7 mRNA levels in macrophages are down-regulated by IL-1␤, LPS, and nicotine. Thus, dup␣7 could modulate ␣7 receptor-mediated synaptic transmission and cholinergic antiinflammatory response.Neuronal ␣7 nicotinic acetylcholine receptors (␣7 nAChRs) 4 are widely expressed in the central and peripheral nervous systems. In neurons, homomeric ␣7 nAChRs, composed of five ␣7 subunits, modulate neurotransmitter release in presynaptic nerve terminals and induce excitatory impulses in postsynaptic neurons (1-4). Signaling through ␣7 nAChRs in the central nervous system has been associated with neuronal plasticity and cell survival (5-7), although impaired activity of this receptor has been implicated in the pathogenesis of schizophrenia, Alzheimer disease, and depression (8 -12). The presence of ␣7 nAChRs has also been reported in non-neuronal cells such as vascular and brain en-

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Section: Discussionsupporting

confidence: 80%

Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene

Lucas-Cerrillo¹,

Maldifassi²,

Arnalich

et al. 2011

Journal of Biological Chemistry

115

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“…However, enhanced CHRNA7 expression did not render human whole blood monocytes more susceptible to nicotinic immunomodulation, which may indicate that the CHRNA7 is not the only mediator effectuating the cholinergic anti-inflammatory effect and another nAChR might be involved. For example, the finding that CHRFAM7A is downregulated in monocytes by LPS challenge, and has been found to be downregulated in smokers’ PBMCs [32] suggests that it could play a role in inflammation by affecting functional α7 nAChRs [14]. This is in conjunction with earlier studies in which it was put forward that receptors of mixed subunits of CHRNA7 and CHRFAM7A are formed that can modulate the signaling potential of immune cells to respond to ACh released from the vagus nerve during infection [12].…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Expression and Susceptibility to Cholinergic Immunomodulation in Human Monocytes of Smoking Individuals

Zanden

Hilbers²,

Verseijden³

et al. 2012

Neuroimmunomodulation

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Objective: Smoking is generally accepted as a factor that affects the disease course in inflammatory bowel disease patients. Whether these effects can be contributed to the immunomodulatory effects of nicotine via nicotinic acetylcholine receptor (nAChR) activation is unclear. As previous data suggest that the α7 nicotinic acetylcholine receptor (CHRNA7) and its duplicated variant CHRFAM7A may specifically participate in the inflammatory response of monocytes, we evaluated whether repeated nicotine exposure or smoking affects monocyte CHRNA7 and CHRFAM7A expression and cholinergic immunomodulation. Methods: The human monocyte cell line THP-I was incubated with nicotine for different time points before endotoxin exposure. In a pilot volunteer study using smoking (n = 4) and nonsmoking (n = 7) individuals, vagal output was stimulated by olive oil administration after which monocytes were analyzed for nicotinic receptor expression. Serum tumor necrosis factor (TNF) levels were determined using ELISA and expression levels of the nAChR subunits CHRNA7, CHRNB2 or CHRFAM7A were analyzed using QPCR. Results: Repeated nicotine exposure upregulated CHRNA7 expression on THP-I monocytes and led to an enhanced potential of α7 nAChR agonist GSK1345038A to reduce TNF levels. Furthermore, CHRNA7 was only detectable in isolated blood monocytes of smokers. On the other hand, the expression of CHRFAM7A and CHRNB2 was not affected by nicotine exposure. Lipopolysaccharides-induced TNF secretion was inhibited by nicotinic receptor activation in THP-I monocytes, but this response was not consistently seen in blood monocytes from smoking individuals. Conclusions: We conclude that CHRNA7 expression on blood monocytes is upregulated in smoking individuals, which may contribute to cholinergic immunomodulation.

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“…None of the splice variants was detected, thereby confirming that dupa7nAChR/ CHRFAM7A Variant 1 is the major transcript in human leukocytes. Furthermore, when analyzing blood from 20 patients, they found that whereas the presence of dupa7nAChR/ CHRFAM7A was readily detectable in human leukocytes, a7nAChR/CHRNA7 was not [76]. Interestingly, they also evaluated dupa7nAChR/CHRFAM7A expression levels in smokers and reported significantly (P , 0.001) decreased dupa7nAChR/CHRFAM7A expression.…”

Section: The Main Chrna7 Transcript Detected By Pcr Of Human Leukocytmentioning

confidence: 99%

“…Four years after Villiger et al [48] identified dupa7nAChR/ CHRFAM7A in human PBMCs, Perl et al [75] would inadvertently confirm the differential expression of dupa7nAChR/ CHRFAM7A and a7nAChR/CHRNA7 in human leukocytes by use of sequence-specific primers that distinguish a7nAChR/ CHRNA7 from dupa7nAChR/CHRFAM7A on human blood samples. Soon thereafter, Severance et al [76] would be the 1st to combine sequence-specific primers and quantitative PCR to quantify a7nAChR/CHRNA7, a7nAChR/CHRNA7 splice variants (e.g., exon 4 deletion, exon 5 deletion, exon 4 and 5 deletion, and exon 4a insertion), and dupa7nAChR/ CHRFAM7A expression in human PBMCs. None of the splice variants was detected, thereby confirming that dupa7nAChR/ CHRFAM7A Variant 1 is the major transcript in human leukocytes.…”

Section: The Main Chrna7 Transcript Detected By Pcr Of Human Leukocytmentioning

confidence: 99%

CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury

Costantini

Dang

Coimbra

et al. 2014

Journal of Leukocyte Biology

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Conventional wisdom presumes that the α7nAChR product of CHRNA7 expression mediates the ability of the vagus nerve to regulate the inflammatory response to injury and infection. Yet, 15 years ago, a 2nd structurally distinct and human-specific α7nAChR gene was discovered that has largely escaped attention of the inflammation research community. The gene, originally called dupα7nAChR but now known as CHRFAM7A, has been studied exhaustively in psychiatric research because of its association with mental illness. However, dupα7nAChR/CHRFAM7A expression is relatively low in human brain but elevated in human leukocytes. Furthermore, α7nAChR research in human tissues has been confounded by cross-reacting antibodies and nonspecific oligonucleotide primers that crossreact in immunoblotting, immunohistochemistry, and RT-PCR. Yet, 3 independent reports show the human-specific CHRFAM7A changes cell responsiveness to the canonical α7nAChR/CHRNA7 ion-gated channel. Because of its potential for the injury research community, its possible significance to human leukocyte biology, and its relevance to human inflammation, we review the discovery and structure of the dupα7nAChR/CHRFAM7A gene, the distribution of its mRNA, and its biologic activities and then discuss its possible role(s) in specifying human inflammation and injury. In light of emerging concepts that point to a role for human-specific genes in complex human disease, the existence of a human-specific α7nAChR regulating inflammatory responses in injury underscores the need for caution in extrapolating findings in the α7nAChR literature to man. To this end, we discuss the translational implications of a uniquely human α7nAChR-like gene on new drug target discovery and therapeutics development for injury, infection, and inflammation.

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Differentiating nicotine- versus schizophrenia-associated decreases of the α7 nicotinic acetylcholine receptor transcript, CHRFAM7A, in peripheral blood lymphocytes

Cited by 14 publications

References 46 publications

Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene

Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene

Nicotinic Acetylcholine Receptor Expression and Susceptibility to Cholinergic Immunomodulation in Human Monocytes of Smoking Individuals

CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury

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