C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity.
The C957T polymorphism of the human dopamine D2 receptor gene (DRD2) regulates DRD2 availability in striatum in vivo. Specifically, the T allele predicts high DRD2 availability in healthy volunteers (T/T>T/C>C/C). However, this finding was unexpected as in vitro the T allele is associated with a decrease in DRD2 mRNA stability and synthesis of the receptor through a putative alteration in the receptor mRNA folding. To elucidate further how changes in DRD2 density (B(max)) and affinity (K(D)) contribute to the differences in DRD2 availability between the C957T genotypes, we studied these parameters separately in a sample of 45 healthy volunteers. The subjects had two PET scans with [(11)C]raclopride (high and low specific radioactivity scans) for the estimation of B(max) and K(D), and were genotyped for the C957T. Moreover, the role of the related and previously studied functional TaqIA polymorphism of ankyrin repeat and kinase domain containing 1 (ANKK1) gene was reassessed for comparative purposes. The results indicate that the C957T increased binding potential by decreasing DRD2 K(D) (C/C>C/T>T/T), while B(max) was not significantly altered. These preliminary findings indicate that the C957T genotype-dependent changes in DRD2 availability are driven by alterations in receptor affinity and putatively in striatal dopamine levels. This mechanism seems to differ from that observed previously for the ANKK1 gene TaqIA polymorphism, where the minor allele (A1) affects DRD2 availability predominantly by changing B(max). The hypothesis that the two SNPs may have independent effects on dopamine neurotransmission needs to be further tested.
Hirvonen
Mika M
MM
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20014 Turku, Finland.
Laakso
Aki
A
Någren
Kjell
K
Rinne
Juha O
JO
Pohjalainen
Tiina
T
Hietala
Jarmo
J
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002247:Carbon Isotopes / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D018709:Statistics, Nonparametric; D055815:Young Adult
D002247:Carbon Isotopes; D017448:Receptors, Dopamine D2; D020891:Raclopride; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases