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 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.
Department of Zoology, College of Life Sciences, Sichuan University, Chengdu, Sichuan Province, 610064, China; Chengdu institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China; Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America.
Qinhui
Q
Zhang
University of California Los Angeles, Henry Samueli School of Engineering and Applied Science, Los Angeles, California 90095, United States of America.
Yingjie
Y
Du
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America; Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders; State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing 100069, China.
Jianliang
J
Zhang
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America.
Xiaojun
X
Xu
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America; Core Facilities for Electrophysiology, Core Facilities Center, Capital Medical University, Beijing 100069, China.
Fenqin
F
Xue
Department of Zoology, College of Life Sciences, Sichuan University, Chengdu, Sichuan Province, 610064, China; Chengdu institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China.
Cong
C
Guo
Department of Obstetrics and Gynecology, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America.
Yao
Y
Huang
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America.
Ronald J
RJ
Lukas
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, United States of America.
Yongchang
Y
Chang
D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D020125:Mutation, Missense; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D019076:Transgenes; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics* / Q000378:metabolism
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C578201:4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinoline-8-sulfonamide; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D011804:Quinolines; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000109:Acetylcholine