Martín-Sánchez, CarolinaAlés, EvaBalseiro-Gómez, SantiagoAtienza, GemaArnalich, FranciscoBordas, AnnaCedillo, José LExtremera, MaríaChávez-Reyes, ArturoMontiel, Carmen2023-05-182023-05-182020-10-22Journal of Biological Chemistry, Vol. 296, January-June (2021) p. 1-15.0021-9258http://hdl.handle.net/20.500.12254/3254Gene duplication generates new functions and traits, enabling evolution. Human-specific duplicated genes in particular are primary sources of innovation during our evo- lution 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 modula- tion of synaptic transmission and plasticity underlying normal attention, cognition, learning, and memory processes. Howev- er, 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 [Ca2+]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 exces- sive, it would result in an impaired synaptic transmission that could underlie the neurocognitive and neuropsychiatric dis- orders associated with α7-nAChR dysfunction.enAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)Dupa7a7-nAChRAncestral α7Nicotinic acetylcholine receptorCHRFAM7ADupα7 subunitArtículohttps://orcid.org/0000-0002-6655-815Xhttps://doi.org/10.1016/j.jbc.2021.100341