TY - JOUR
T1 - The piccolo intronic single nucleotide polymorphism rs13438494 regulates dopamine and serotonin uptake and shows associations with dependence-like behavior in genomic association study
AU - Uno, K.
AU - Nishizawa, D.
AU - Seo, S.
AU - Takayama, K.
AU - Matsumura, S.
AU - Sakai, N.
AU - Ohi, K.
AU - Nabeshima, T.
AU - Hashimoto, R.
AU - Ozaki, N.
AU - Hasegawa, J.
AU - Sato, N.
AU - Tanioka, F.
AU - Sugimura, H.
AU - Fukuda, K. I.
AU - Higuchi, S.
AU - Ujike, H.
AU - Inada, T.
AU - Iwata, N.
AU - Sora, I.
AU - Iyo, M.
AU - Kondo, N.
AU - Won, M. J.
AU - Naruse, N.
AU - Uehara-Aoyama, K.
AU - Itokawa, M.
AU - Yamada, M.
AU - Ikeda, K.
AU - Miyamoto, Y.
AU - Nitta, A.
N1 - Publisher Copyright:
© 2015 Bentham Science Publishers.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84929622211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929622211&partnerID=8YFLogxK
U2 - 10.2174/1566524015666150330145722
DO - 10.2174/1566524015666150330145722
M3 - Article
C2 - 25817861
AN - SCOPUS:84929622211
SN - 1566-5240
VL - 15
SP - 265
EP - 274
JO - Current Molecular Medicine
JF - Current Molecular Medicine
IS - 3
ER -