Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene POTENTIAL IMPLICATIONS FOR THE CHOLINERGIC ANTI-INFLAMMATORY RESPONSE

The neuronal alpha 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 alpha 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 alpha 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 alpha 7 transcript was natively translated in HL-60 cells and heterologously expressed in GH4C1 cells and oocytes. Injection of dup alpha 7 mRNA into oocytes failed to generate functional receptors, but when co-injected with alpha 7 mRNA at alpha 7/dup alpha 7 ratios of 5:1, 2:1, 1:1, 1:5, and 1: 10, it reduced the nicotine-elicited alpha 7 current generated in control oocytes (alpha 7 alone) by 26, 53, 75, 93, and 94%, respectively. This effect is mainly due to a reduction in the number of functional alpha 7 receptors reaching the oocyte membrane, as deduced from alpha-bungarotoxin binding and fluorescent confocal assays. Two additional findings open the possibility that the dominant negative effect of dup alpha 7 on alpha 7 receptor activity observed in vitro could be extrapolated to in vivo situations. (i) Compared with alpha 7 mRNA, basal dup alpha 7 mRNA levels are substantial in human cerebral cortex and higher in macrophages. (ii) dup alpha 7 mRNA levels in macrophages are down-regulated by IL-1 beta, LPS, and nicotine. Thus, dup alpha 7 could modulate alpha 7 receptor-mediated synaptic transmission and cholinergic anti-inflammatory response.