摘要
短笛(PCLO)抑制甲基苯丙胺诱导的神经药理学作用通过调节多巴胺(DA)摄取和神经元突触泡的运输的调节。最近的临床研究表明,在GWAS的荟萃分析中,PCLO基因的内含子24的单核苷酸多态性(SNP)rs13438494与精神疾病相关。因此,在本研究中,我们尝试着去评价PCLO SNP在单胺摄取的机制中所可能发挥的作用。为了表征PCLO基因rs13438494,我们构建了携带SNP C或A等位基因的质粒,且瞬时将其转染成SH-SY5Y细胞来分析PCLO mRNA的剪接遗传效应。C和A等位基因构建体产生了不同的转录物组合物,表明该内含子的SNP确实影响剪接模式。我们也转染了DA和血清素(5-羟色胺;5-HT)转运蛋白到细胞内,并分析了它们的摄取,以阐明其与精神疾病的关联。在转染的C等位基因的细胞中,与A等位基因相比,DA和5-HT的摄取都增强了。我们还进行了临床研究,以阐明遗传关联。PCLO rs13438494显示出药物依赖或相关参数的症状,如第一次接触到冰毒、饮食失调、烟草依赖和芬太尼需求。我们的研究结果表明,rs13438494与药物滥用有关,并通过神经递质翻转的调节有利于精神疾病的发病机制。
关键词: 依赖性行为,多巴胺,短笛,血清素,单核甘酸多态性
Current Molecular Medicine
Title:The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study
Volume: 15 Issue: 3
Author(s): K. Uno, D. Nishizawa, S. Seo, K. Takayama, S. Matsumura, N. Sakai, K. Ohi, T. Nabeshima, R. Hashimoto, N. Ozaki, J. Hasegawa, N. Sato, F. Tanioka, H. Sugimura, K.-I.- Fukuda, S. Higuchi, H. Ujike, T. Inada, N. Iwata, I. Sora, M. Iyo, N. Kondo, M.-J. Won, N. Naruse, K. Uehara-Aoyama and M. Itokawa, M. Yamada, K. Ikeda, Y. Miyamoto and A. Nitta
Affiliation:
关键词: 依赖性行为,多巴胺,短笛,血清素,单核甘酸多态性
摘要: Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.
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K. Uno, D. Nishizawa, S. Seo, K. Takayama, S. Matsumura, N. Sakai, K. Ohi , T. Nabeshima, R. Hashimoto, N. Ozaki, J. Hasegawa, N. Sato, F. Tanioka, H. Sugimura, K.-I.- Fukuda , S. Higuchi, H. Ujike, T. Inada, N. Iwata, I. Sora, M. Iyo, N. Kondo, M.-J. Won, N. Naruse, K. Uehara-Aoyama and M. Itokawa, M. Yamada, K. Ikeda, Y. Miyamoto and A. Nitta , The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study, Current Molecular Medicine 2015; 15 (3) . https://dx.doi.org/10.2174/1566524015666150330145722
DOI https://dx.doi.org/10.2174/1566524015666150330145722 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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