The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7nAChR function

• Published in: Biochemical pharmacology 2011-10, Vol.82 (8), p.904-914
• Main Authors: Araud, Tanguy, Graw, Sharon, Berger, Ralph, Lee, Michael, Neveu, Estele, Bertrand, Daniel, Leonard, Sherry
• Format: Article
• Language: English
• Subjects: acetylcholine; Adult and adolescent clinical studies; Allosteric Regulation - drug effects; alpha7 Nicotinic Acetylcholine Receptor; Animals; Biological and medical sciences; brain; Bungarotoxins - pharmacology; cations; Cell Line, Tumor; central nervous system diseases; chimerism; CHRFAM7A; CHRNA7; Cloning, Molecular; cognition; duplicate genes; Electrophysiological Phenomena; evolution; Female; gene expression regulation; Genes, Duplicate; Genetic Linkage; Humans; Isoxazoles - pharmacology; Ligands; Medical sciences; Multigene Family; Nicotinic receptor; Oocytes; Patch-Clamp Techniques; patients; Pharmacology. Drug treatments; Phenylurea Compounds - pharmacology; Protein Binding; protein synthesis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; receptors; Receptors, Nicotinic - genetics; Receptors, Nicotinic - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA - genetics; Schizophrenia; Schizophrenia - genetics; Smoking - genetics; synaptic transmission; Transfection; Xenopus; Xenopus laevis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.06.018

The human α7 neuronal nicotinic acetylcholine receptor gene ( CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the α7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca 2+, that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of α7*nAChR, as measured by binding of the ligand [ 125I]-α-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene ( CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2 bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of α7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with α7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.