Role of silent polymorphisms within the dopamine D1 receptor associated with schizophrenia on D1-D2 receptor hetero-dimerization.
Journal Title: Pharmacological Reports - Year 2009, Vol 61, Issue 6
Abstract
Within the coding region of the dopamine D(1) receptor (D(1)R), two synonymous polymorphisms, D(1)R(G198A) and D(1)R(G1263), have been identified and postulated to correlate with the schizophrenia phenotype. Binding studies revealed that the density of these genetic variants was much lower than the density of wild type D(1)R in the human embryonic kidney (HEK) 293 cell line, used as a model system. From the data obtained using MFOLD software it is apparent that the G198A mutation has a greater impact on the secondary structure of the mRNA, which may affect its translation. However, the G1263A mutation is localized within the serine 421 codon of D(1)R, which is predicted to be a potential site of phosphorylation according to the PHOSIDA database. In order to determine whether the studied synonymous polymorphisms influence the process of dopamine D(1)-D(2) receptors heterodimerization, we employed fluorescence resonance energy transfer (FRET) technology. The dopamine D(2) receptor (D(2)R) was tagged with cyan fluorescence protein and the D(1)R and its genetic variants were tagged with yellow fluorescence protein. The degree of D(1)-D(2) receptor hetero-dimerization was significantly decreased when genetic variants of D(1)R were co-expressed with D(2)R. Since the D(1)R mutations affected the expression levels of the proteins in the cell membrane without affecting the cellular localization of the receptor proteins, we postulated that the D(1)R polymorphisms altered the translation rate and protein structure of the receptor. The altered hetero-dimerization that likely results from the lower expression of these genetic variants of D(1)R with D(2)R may be partially responsible for the association of both G198A and G1263A polymorphisms with the schizophrenia phenotype.
Authors and Affiliations
Katarzyna Grymek, Sylwia Łukasiewicz, Agata Faron-Górecka, Magdalena Tworzydlo, Agnieszka Polit, Marta Dziedzicka-Wasylewska
Keywords
Related Articles
- EP ID EP134212
- DOI -
- Views 91
- Downloads 0
Hormonal supplementation in endocrine dysfunction in critically ill patients.
One of the greatest challenges for a physician is a critically ill patient. Regardless of the reason for an admission to the Intensive Care Units (ICU) (e.g. myocardial infarction, severe pneumonia, trauma or many others...
Frequency of common CYP3A5 gene variants in healthy Polish newborn infants.
Cytochrome P450 monooxygenases catalyze the metabolism of approximately 40-60% of widely used drugs with a A6986G CYP3A5 polymorphism determining expresser (A6986, *1) and reduced- expresser (*3) variants with modified d...
Effect of repeated co-treatment with imipramine and metyrapone on the behavioral reactivity of the central serotonin, dopamine and alpha(1)-adrenergic systems in rats.
The aim of present study was to examine the effect of repeated co-treatment with imipramine and metyrapone on the development of adaptive changes in the function of central serotonin 5-HT(1A) and 5-HT(2A), dopamine D(2/3...
Enhanced oxidative stress in hypertrophic cardiomyopathy.
Elevated plasma levels of inflammation and endothelial dysfunction markers have been reported in patients with hypertrophic cardiomyopathy (HCM). The aim of the current study was to determine whether HCM is associated wi...
Mebeverine influences sodium ion transport in the distal colon.
The study was performed to check if the well-known intestinal spasmolytic effect of mebeverine is paralleled by any changes in intestinal transepithelial currents. The transepithelial potential difference related to ioni...