![]() Molas, Susanna Gener, Thomas Güell, Jofre MartÃn, Mairena Ballesteros-Yáñez, Inmaculada Sanchez-Vives, Maria V Dierssen, MaraĪddiction involves long-lasting maladaptive changes including development of disruptive drug-stimuli associations. Hippocampal changes produced by overexpression of the human CHRNA5/A3/B4 gene cluster may underlie cognitive deficits rescued by nicotine in transgenic mice. These results suggest that CHRFAM 7A acts as a dominant negative modulator of CHRNA 7 function and is critical for receptor regulation in humans. 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. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. Expression of the duplicate alone yielded protein expression but no functional receptor and co- expression with α 7 caused a significant reduction of the amplitude of the ACh-evoked currents. To examine the putative contribution of CHRFAM 7A on receptor function, co- expression of α 7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. The association between a 2bp deletion in CHRFAM 7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. During evolution, CHRNA 7 was partially duplicated as a chimeric gene (CHRFAM 7A), which is expressed in the human brain and elsewhere in the body. The structure of the gene, CHRNA 7, is complex. Schizophrenic patients have low levels of α 7*nAChR, as measured by binding of the ligand -α-bungarotoxin (I-BTX). Activation of the α 7*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. ![]() The human α 7 neuronal nicotinic acetylcholine receptor gene ( CHRNA 7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. The chimeric gene CHRFAM 7A, a partial duplication of the CHRNA 7 gene, is a dominant negative regulator of α 7*nAChR function.Īraud, Tanguy Graw, Sharon Berger, Ralph Lee, Michael Neveu, Estele Bertrand, Daniel Leonard, Sherry
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