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

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 (dup alpha 7 subunit). This gene results from a partial duplication of the ancestral CHRNA7 gene encoding the alpha 7 subunit that forms the homopentameric alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR). The functions of alpha 7-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 dup alpha 7 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 alpha 7-nAChR activity using human neuroblastoma SH-SY5Y cell variants with different dup alpha 7 expression levels. Our findings reveal a physical interaction between dup alpha 7 and alpha 7 subunits in fluorescent protein-tagged dup alpha 7/alpha 7 transfected cells that negatively affects normal alpha 7-nAChR activity. Specifically, in both single cells and cell populations, the [Ca2+] i signal and the exocytotic response induced by selective stimulation of alpha 7-nAChR were either significantly inhibited by stable dup alpha 7 overexpression or augmented after silencing dup alpha 7 gene expression with specific siRNAs. These findings identify a new role for the dup alpha 7 subunit as a negative regulator of alpha 7-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 alpha 7-nAChR dysfunction.