CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor

Chan, Theresa W.; Williams, Elliot; Cohen, Ornit; Eliceiri, Brian P.; Baird, Andrew; Costantini, Todd W.

doi:10.1016/j.neulet.2018.10.010

Cited by 17 publications

(18 citation statements)

References 22 publications

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“…Based on the above data as well as on previous findings by our group and others in Xenopus oocytes and in several mammalian cell lines, such as neuroendocrine GH4C1, immune RAW264.7, BOSC-23 kidney, or human NSCLC cells ( 36 , 37 , 39 , 54 , 55 ), we propose that dupα7 subunits could be colocated with full-length α7 subunits in SH-SY5Y cells forming heteromeric dupα7/α7-nAChRs to the detriment of fully functional homomeric α7-nAChR expression. If our proposal is true, then overexpression of dupα7 in SH-SY5Y cells would result in a decreased cellular responsiveness to α7-nAChR stimulation.…”

Section: Discussionsupporting

confidence: 64%

The human-specific duplicated α7 gene inhibits the ancestral α7, negatively regulating nicotinic acetylcholine receptor-mediated transmitter release

Martín-Sánchez

Alés

Balseiro-Gómez

et al. 2021

Journal of Biological Chemistry

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Gene duplication generates new functions and traits, enabling evolution. Human-specific duplicated genes in particular are primary sources of innovation during our evolution although they have very few known functions. Here we examine the brain function of one of these genes ( CHRFAM7A ) and its product (dupα7 subunit). This gene results from a partial duplication of the ancestral CHRNA7 gene encoding the α7 subunit that forms the homopentameric α7 nicotinic acetylcholine receptor (α7-nAChR). The functions of α7-nAChR in the brain are well defined, including the modulation of synaptic transmission and plasticity underlying normal attention, cognition, learning, and memory processes. However, the role of the dupα7 subunit remains unexplored at the neuronal level. Here, we characterize that role by combining immunoblotting, quantitative RT-PCR and FRET techniques with functional assays of α7-nAChR activity using human neuroblastoma SH-SY5Y cell variants with different dupα7 expression levels. Our findings reveal a physical interaction between dupα7 and α7 subunits in fluorescent protein-tagged dupα7/α7 transfected cells that negatively affects normal α7-nAChR activity. Specifically, in both single cells and cell populations, the [Ca 2+ ] i signal and the exocytotic response induced by selective stimulation of α7-nAChR were either significantly inhibited by stable dupα7 overexpression or augmented after silencing dupα7 gene expression with specific siRNAs. These findings identify a new role for the dupα7 subunit as a negative regulator of α7-nAChR-mediated control of exocytotic neurotransmitter release. If this effect is excessive, it would result in an impaired synaptic transmission that could underlie the neurocognitive and neuropsychiatric disorders associated with α7-nAChR dysfunction.

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Section: Discussionsupporting

confidence: 64%

The human-specific duplicated α7 gene inhibits the ancestral α7, negatively regulating nicotinic acetylcholine receptor-mediated transmitter release

Martín-Sánchez

Alés

Balseiro-Gómez

et al. 2021

Journal of Biological Chemistry

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“…α-BTX showed very low binding affinity to all the receptors containing Dupα7 subunits ( Table 2), suggesting that those receptors will be resistant to α-BTX. This observation agrees with the published experimental data showing that CHRFAM7A decreased α-BTX binding as detected by immunohistochemistry and flow cytometry and markedly decreased α-BTX staining neuromuscular junction of CHRFAM7A transgenic mice (Chan et al, 2019).…”

Section: The Effect Of Dupα7 Subunits On Macromolecular Ligand Bindingsupporting

confidence: 93%

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders

Liu¹,

Cunha²,

Ahmed³

et al. 2021

Preprint

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<p>Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 has a negative effect on the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/ α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/ dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ42. Our findings show that the optimal stoichiometry of dupα7/ α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in Alzheimer's Disease research. </p>

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“…Nearly 20 y ago, the possibility that taxonomically restricted genes specify species-specific responsiveness garnered attention with the discovery of cmah (7), a gene whose product is absent in humans but nevertheless regulates resilience, susceptibility, and the response to infection and injury in other species (8, 61, 62). The present study with CHRFAM7A in transgenic mice was made possible because we were first able to show that CHRFAM7A recognizes and regulates the mouse form of α7nAChR (19). We posit that it is this interaction that most likely generates the HSC phenotype reported here and predict that CHRNA7 knockout mice could have the same phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have suggested that CHRFAM7A encodes a dominant-negative inhibitor of ligand binding to α7nAChR in vitro (15–18), which can also be observed at the neuromuscular junction of transgenic mice (19). As such, CHRFAM7A has been implicated in the regulation of numerous α7nAChR-dependent antiinflammatory processes as well as in mental health, cognition, and neurodegenerative disease (20).…”

mentioning

confidence: 99%

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response

Costantini

Chan

Cohen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease.

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CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor

Cited by 17 publications

References 22 publications

The human-specific duplicated α7 gene inhibits the ancestral α7, negatively regulating nicotinic acetylcholine receptor-mediated transmitter release

The human-specific duplicated α7 gene inhibits the ancestral α7, negatively regulating nicotinic acetylcholine receptor-mediated transmitter release

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response

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