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.
Keywords: Dependence-like behavior, dopamine, Piccolo, serotonin, single nucleotide polymorphism.
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