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Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor

The α7nicotinic receptor (nAChR) is a major subtype of the nAChRs in the central nervous system, and the receptor plays an important role in brain function. In the dbSNP database, there are 55 single nucleotide polymorphisms (SNPs) that cause missense mutations of the human α7nAChR in the coding reg...

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Autores principales: Zhang, Qinhui, Du, Yingjie, Zhang, Jianliang, Xu, Xiaojun, Xue, Fenqin, Guo, Cong, Huang, Yao, Lukas, Ronald J., Chang, Yongchang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560414/
https://www.ncbi.nlm.nih.gov/pubmed/26340537
http://dx.doi.org/10.1371/journal.pone.0137588
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author Zhang, Qinhui
Du, Yingjie
Zhang, Jianliang
Xu, Xiaojun
Xue, Fenqin
Guo, Cong
Huang, Yao
Lukas, Ronald J.
Chang, Yongchang
author_facet Zhang, Qinhui
Du, Yingjie
Zhang, Jianliang
Xu, Xiaojun
Xue, Fenqin
Guo, Cong
Huang, Yao
Lukas, Ronald J.
Chang, Yongchang
author_sort Zhang, Qinhui
collection PubMed
description The α7nicotinic receptor (nAChR) is a major subtype of the nAChRs in the central nervous system, and the receptor plays an important role in brain function. In the dbSNP database, there are 55 single nucleotide polymorphisms (SNPs) that cause missense mutations of the human α7nAChR in the coding region. In this study, we tested the impact of 14 SNPs that cause missense mutations in the agonist binding site or the coupling region between binding site and channel gate on the receptor function. The wild type or mutant receptors were expressed or co-expressed in Xenopus oocytes, and the agonist-induced currents were tested using two-electrode voltage clamp. Our results demonstrated that 6 mutants were nonfunctional, 4 mutants had reduced current expression, and 1 mutants altered ACh and nicotine efficacy in the opposite direction, and one additional mutant had slightly reduced agonist sensitivity. Interestingly, the function of most of these nonfunctional mutants could be rescued by α7nAChR positive allosteric modulator PNU-120596 and agonist-PAM 4BP-TQS. Finally, when coexpressed with the wild type, the nonfunctional mutants could also influence the receptor function. These changes of the receptor properties by the mutations could potentially have an impact on the physiological function of the α7nAChR-mediated cholinergic synaptic transmission and anti-inflammatory effects in the human SNP carriers. Rescuing the nonfunctional mutants could provide a novel way to treat the related disorders.
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spelling pubmed-45604142015-09-10 Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor Zhang, Qinhui Du, Yingjie Zhang, Jianliang Xu, Xiaojun Xue, Fenqin Guo, Cong Huang, Yao Lukas, Ronald J. Chang, Yongchang PLoS One Research Article The α7nicotinic receptor (nAChR) is a major subtype of the nAChRs in the central nervous system, and the receptor plays an important role in brain function. In the dbSNP database, there are 55 single nucleotide polymorphisms (SNPs) that cause missense mutations of the human α7nAChR in the coding region. In this study, we tested the impact of 14 SNPs that cause missense mutations in the agonist binding site or the coupling region between binding site and channel gate on the receptor function. The wild type or mutant receptors were expressed or co-expressed in Xenopus oocytes, and the agonist-induced currents were tested using two-electrode voltage clamp. Our results demonstrated that 6 mutants were nonfunctional, 4 mutants had reduced current expression, and 1 mutants altered ACh and nicotine efficacy in the opposite direction, and one additional mutant had slightly reduced agonist sensitivity. Interestingly, the function of most of these nonfunctional mutants could be rescued by α7nAChR positive allosteric modulator PNU-120596 and agonist-PAM 4BP-TQS. Finally, when coexpressed with the wild type, the nonfunctional mutants could also influence the receptor function. These changes of the receptor properties by the mutations could potentially have an impact on the physiological function of the α7nAChR-mediated cholinergic synaptic transmission and anti-inflammatory effects in the human SNP carriers. Rescuing the nonfunctional mutants could provide a novel way to treat the related disorders. Public Library of Science 2015-09-04 /pmc/articles/PMC4560414/ /pubmed/26340537 http://dx.doi.org/10.1371/journal.pone.0137588 Text en © 2015 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhang, Qinhui
Du, Yingjie
Zhang, Jianliang
Xu, Xiaojun
Xue, Fenqin
Guo, Cong
Huang, Yao
Lukas, Ronald J.
Chang, Yongchang
Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title_full Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title_fullStr Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title_full_unstemmed Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title_short Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor
title_sort functional impact of 14 single nucleotide polymorphisms causing missense mutations of human α7 nicotinic receptor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560414/
https://www.ncbi.nlm.nih.gov/pubmed/26340537
http://dx.doi.org/10.1371/journal.pone.0137588
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