• 생물정신의학
• /
• 제9권1호
• /
• pp.15-24
• /
• 2002

Even though alcoholism is a multi-factorial psychiatric disorder, it is reasonable to suppose that genetic factors play a substantial role in the manifestation of this disorder. Because alcohol is the reinforcing substance which manifests its effects through activation of the mesolimbic dopaminergic reward pathway of the brain, the gene encoding dopamine receptor subtypes can be a major natural candidate gene. Since 1990, many association studies have identified strong evidence implicating the dopamine D2 receptor(DRD2) gene in alcoholism, specifically TaqI A minor(A1) allele. Association studies have also been conducted on other dopamine receptor(DRD3 & DRD4) polymorphisms but the results have yet to be confirmed. Through a number of other approaches, each dopamine receptor gene has been investigated in association with different phenotypes in alcoholism, but further researches will be needed. In conclusion, studies in the past decade have shown that the TaqI A1 allele of the DRD2 gene is associated with alcoholism in various subject groups. Other dopamine receptor genes have since been added to the list but yet to be identified. Thus, the knowledge of these genes and their functional significance will enhance the understanding of the underlying biological mechanisms of alcoholism. Furthermore, it could lead to more helpful prevention and treatment approaches to alcoholism.

• Archives of Pharmacal Research
• /
• 제19권4호
• /
• pp.275-279
• /
• 1996

To study the functional roles of dopamine receptors, we decided to raise antibodies against these proteins. To make antigen, we expressed the whole 3rd cytoplasmic loop of dopamine receptors in a fusion protein with glutathione-S-transferase (GST). $For D_2\; and\; D_3$ receptors, it was successful to express and purify fusion proteins for the whole 3rd cytoplasmic loops. However, we could not express the fusion protein for the whole 3rd cytoplasmic loop of $D_4$ dopamine receptor in the bacteria. To study the causes that prevent the bacterial expression of the GST-fusion protein of the 3rd cytoplasmic loop of $D_4$ dopamine receptor, we conducted more detailed studies on $D_4$ dopamine receptor. To locate the region which prevents bacterial expression, we made sequential constructs in the 3rd cytoplasmic loop decreasing the size step by step, and confirmed their expressions in the SDS PAGE. It was found that certain regions of 3rd cytoplasmic loop of $D_4$ dopamine receptor, located in N-terminal side of the 3rd cytoplasmic loop of $D_4$ dopamine receptor suppress the bacterial expression of fusion protein.

• 생물정신의학
• /
• 제8권2호
• /
• pp.246-250
• /
• 2001

The dopamine D4 receptor gene has a hypervariable segment in the coding region characterized by a varying number of 48bp repeats in exon III of the gene. Varying the numbers of repeated segments may change the length, structure, and function of the receptor, which makes this gene a possible candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. We evaluated the dopamine D4 receptor genotype in male alcoholics and normal controls. All alcoholics and controls were unrelated and from the Korean population. Genotype and allele frequencies in 67 alcoholics were compared to 67 controls who were free of alcohol abuse, substance abuse, and major mental illness. No association was found between the dopamine D4 receptor allele and alcoholism. This result indicate that there is no association of the dopamine D4 receptor with alcoholism in Korean. Further systemized investigation to determine the role of dopamine D4 receptor gene in alcoholism with a larger sample size will be required.

• 생물정신의학
• /
• 제2권1호
• /
• pp.57-62
• /
• 1995

항정신병 약물인 clozapine이 주로 작용하는 도파민 수용체로 알려진 도파민 $D_4$ 수용체는 각각 50 염기쌍에 해당하는 크기의 차이가 있음이 알려져 PCR을 이용해 정신분열증 환자와 정상대조군을 대상으로 도파민 $D_4$ 수용체 유전자의 대립형질 분포를 알아보았다. 정신분열증 환자군과 대조군 모두에 있어 여섯종류의 대립형질의 관찰되었으며 정신분열증 환자에서 네번 반복형태의 대립형질이 수적으로 더 많이 관찰되었지만 통계적으로 유의한 차이는 없었으며 정신분열증과 관련된 도파민 $D_4$ 수용체 유전자의 대립형질은 확인되지 않았다. 그러나 보다 객관적인 정보를 얻기 위해서 clozapine에 대한 반응에 따라 정신분열증 환자의 아형을 분류하고 그 아형에 따른 도파민 $D_4$ 수용체 유전자 대립형질분포의 차이에 관한검증이 필요하며, 나아가 도파민 $D_4$ 수용체 유전자의 발현에 있어 정신분열증 환자와 정상인에 차이가 있는지 여부를 밝히는 추적연구가 필요할 것으로 사료된다.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
• /
• pp.89.1-89.1
• /
• 2003

The signaling pathway of dopamine D$_2$ receptor was studied using yeast two-hybrid system. The 3rd cytoplasmic loop of rat D$_2$ receptor was fond to interact with ALY. The interaction in the yeast was observed only with the 3rd cytoplasmic loop of D$_2$ receptor but not with that of D$_3$ or D$_4$ dopamine receptor. The interaction between two proteins was also confirmed by GST pull-down assay. Co-expression of D$_2$ receptor and ALY enhanced the expression of Lef-1 promoter in C6 cells and the promoter of D$_2$ dopamine receptor itself.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
• /
• pp.270.1-270.1
• /
• 2002

The signaling pathway of D2 dopamine receptor was studied using yeaslt two-hybrid system.. The 3rd cytoplasmic loop of rat D2 dopamine receptor was used to screen the cDNA library of mouse brain. and ALY was found to interact with it. The interaction in the yeast was observed only with the 3rd cytoplasmic loop of D2 dopamine receptor but not with that of D3 or D4 dopamine receptor. The interaction between two proteins was also confirmed by GST pull-down assay. (omitted)

• Archives of Pharmacal Research
• /
• 제25권2호
• /
• pp.202-207
• /
• 2002

This study was performed to investigate the effect of tetrahydroisoxazolopyridine (THIP), a $GABA_A$ agonist, on the morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice. A single administration of morphine induced hyperactivity in mice. However, the morphine-induced hyperactivity was inhibited dose-dependently by the administration of THIP (0.2, 0.4 and 0.8 mg/kg, i.p.). In contrast, daily administration of morphine resulted in a reverse tolerance to the hyperactivity caused by morphine (10 mg/kg ,s.c.). THIP inhibited the development of reverse tolerance in the mice that had received the repeated same morphine (10 mg/kg s.c.) doses. The postsynaptic dopamine receptor supersensitivity, which was evidenced by the enhanced ambulatory activity its after the administration of apomorphine (2 mg/kg s.c.), also developed in the reverse tolerant mice. THIP also inhibited the development of the postsynaptic dopamine receptor supersensitivity indulged by the chronic morphine administration. These results suggest that the hyperactivity, reverse toterance and postsynaptic dopamine receptor supersensitivity induced by morphine can be inhibited activating the $GABA_A$ receptors.

• 생물정신의학
• /
• 제4권2호
• /
• pp.218-224
• /
• 1997

The results regarding an association between the polymorphism sites in the dopamine $D_1$ receptor gene and schizophrenia compelled us to study the distribution of the polymorphism in Korean schizophrenia and controls. Eighty-eight schizophrenic patients and normal controls were examined by case-control study for distribution of the polymorphism of the dopamine $D_1$ receptor gene in Korean popualtion to minimize the effect of racial differencies in gene frequencies. The frequencies of the $B_1$ and $B_2$ in schizophrenic patients were 0.11 and 9.89, respectively. And 0.10 and 0.90 in normal control. Ther was no significant differences in the frequencies in the allele $B_1$ and $B_2$between schizophrenic patients and normal controls. The author present here the evidence of a lack of alleic association between the polymorphism of the dopamine $D_1$ receptor gene and Korean schizophrenic patients. The assumption that the dopamine $D_1$ receptor gene has a genetic role in the development of schizophrenia was not suppoorted by this case-control study.

• Biomolecules & Therapeutics
• /
• 제2권1호
• /
• pp.16-22
• /
• 1994

Using 2 to 4 day-old postnatal rats, primary brain cell cultures were made from various brain regions (substantia nigra, hippocampus, striatum, and nucleus accumbens). Whole-cell patch clamp technique was used for electrophysiological studies. Neurons cultured from substantia nigra were characterized more in detail to test whether these cultured neurons were appropriate for physiological studies. Immunocytochemical and electrophysiological properties of these cultured neurons agreed with those from other in vivo or in vitro studies suggesting that cultured neurons maintained normal cytological and physiological conditions. Modulation of ionic channels through dopamine receptors were studied from brain areas where dopamine plays important roles on brain functions. When neurons were clamped near resting membrane potential (-74mV), R(+), R(+)-SKF 38393, a specific D$_1$receptor agonist, activated cultured striatal neurons, and dopamine itself produced biphasic responses. Responses of cultured hippocampal neurons to dopamine agonists were kinds of mirror images to those from striatal neurons; D$_1$receptor agonists inhibited hippocampal neurons but quinpirole, a D$_2$receptor agonist, activated them. Neurons cultured from nucleus accumbens were inhibited by dopamine.

• Biomolecules & Therapeutics
• /
• 제27권6호
• /
• pp.514-521
• /
• 2019

G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished ${\beta}$-arrestin-mediated desensitization, resulting in increased Gs signaling.