Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

Cravchik, Anibal; Sibley, David R.; Gejman, Pablo V.

doi:10.1074/jbc.271.42.26013

Cited by 119 publications

(80 citation statements)

References 33 publications

(28 reference statements)

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“…Ser311Cys in DRD2 has been reported to be associated with a reduced ability of activating the appropriate Gi-like protein [133]. Brain imaging studies of healthy volunteers have shown that individuals with an A1 allele (C allele of C32806T) of DRD2 have a reduced number of dopamine D2 receptors [134,135]. The DRD3 Ser9Gly genotypes were reported to differ with regard to their dopamine-binding affinity [136].…”

Section: Genetic Epidemiologymentioning

confidence: 99%

Molecular epidemiology of major depressive disorder

Kiyohara

Yoshimasu

2009

Environ Health Prev Med

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Major depressive disorder causes significant morbidity, affecting people's ability to work, function in relationships, and engage in social activities. Moreover, major depressive disorder increases the risk of suicidal ideation, attempted suicide and death by completed suicide. There is evidence that chronic stress can cause major depressive disorder. As for genetic factors, only minor susceptibility genes have been reliably identified. The serotonin system provides a logical source of susceptibility genes for depression, because this system is the target of selective serotonin reuptake-inhibitor drugs that are effective in treating depression. The 5-hydroxytryptamine (serotonin) transporter (5-HTT) has received particular attention because it is involved in the reuptake of serotonin at brain synapses. One common polymorphic variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which affects the promoter of the 5-HTT gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. The authors discussed the relationship between genetic polymorphisms and major depressive disorder, with special emphasis on the 5-HTTTLPR polymorphism. As the 5-HTTLPR polymorphism was significantly associated with an increased risk of major depressive disorder, the 5-HTT gene may be a candidate for a major depressive disorder susceptibility gene. As major depressive disorder is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for major depressive disorder. Hopefully, in the future we will be able to screen for major depressive disorder susceptibility by using specific biomarkers.

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Section: Genetic Epidemiologymentioning

confidence: 99%

Molecular epidemiology of major depressive disorder

Kiyohara

Yoshimasu

2009

Environ Health Prev Med

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“…24 This amino acid change occurs in the third intracellular loop and has been shown to substantially impair downstream signal transduction from the DRD2 receptor in cultured mammalian cells (CHO-K1), apparently via reduced activation of the appropriate G-protein which in turn leads to decreased inhibition of cAMP production. 25 TaqIA is a T to C transition in the 3 H non-coding region of the gene, 10.5 kb downstream of the stop codon and 9.4 kb downstream of the polyA signal. It was used in the earlier studies of association of DRD2 with obesity.…”

Section: Introductionmentioning

confidence: 99%

Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians

et al. 2000

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OBJECTIVES: To investigate whether (a) variants within the dopamine D2 receptor gene (DRD2) are associated with obesity and type 2 diabetes in Pima Indians, and (b) whether variation in this gene could be responsible for previously observed linkage to these phenotypes, at chromosome location 11q23 ± 24, in this population. DESIGN: Two single nucleotide polymorphisms (SNPs), Ser311Cys and TaqIA, within the DRD2 gene were genotyped by allelic discrimination PCR in subjects who had provided evidence of linkage to diabetes and obesity in an autosome-wide scan. SUBJECTS: A total of 1187 subjects were genotyped, including 947 full heritage Pima Indians (80%). Descriptive statistics for all subjects analyzed, for whom clinical data were available, were (mean AE s.d.): age at time of last exam 41 AE 15 y; birth year 1950 AE 14; age-sex-adjusted body mass index (BMI; adjusted to a mean age of 35 y) 36 AE 8 kgam 2 ; male 44%; diabetic 57%. For full heritage Pimas only: age 43 AE 15 y; birth year 1948 AE 14; sex ± age-adjusted BMI 36 AE 8 kgam 2 ; male 43%; diabetic 59%. RESULTS: Neither polymorphism was signi®cantly associated with diabetes in full heritage Pimas. Individuals with à CG' genotype at the Ser311Cys SNP had a higher BMI than those with a`CC' genotype (36.7 vs 35.5 kgam 2 , P 0.04). Linkage analysis of BMI, adjusted for either polymorphism, resulted in LOD scores that were similar to those obtained without adjustment. CONCLUSION: Heterozygotes at the Ser311Cys DRD2 polymorphism had a slightly higher BMI than homozygotes, however neither the Ser311Cys nor the TaqIA polymorphism accounted for the linkage with BMI on chromosome 11 in Pima Indians.

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“…See Table 1 for number and ages of subjects. 9 Although, second messenger 19 and sequestration 20 alterations may be associated with the Ser 311 →Cys variant, these variants do not appear to be associated with altered D 2 receptor-binding characteristics in vitro 10,19 or in vivo. 10 This supports the view that the missense substitutions in the D 2 receptor do not affect antagonistbinding properties, and therefore, an alteration in K d due to the structural changes of the receptor protein was unlikely a priori.…”

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confidence: 99%

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

et al. 1998

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Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D 2 receptor density in vivo in human striatum. 1 Low D 2 receptor binding in vivo has been found to associate with alcohol/substance dependence. [2][3][4][5][6] It has been suggested that the A1 allele of human D 2 receptor gene might be associated to a specific type of alcoholism 7 and possibly to a reduced D 2 receptor density in vitro. 8 We have determined D 2 dopamine receptor-binding density (B max ), affinity (K d ) and availability (B max /K d ) in 54 healthy Finnish volunteers using PET and [ 11 C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D 2 receptor characteristics in vivo. A statistically significant reduction in D 2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent K d between the two groups. In conclusion, the association between the A1 allele and low D 2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D 2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.The dopaminergic system plays a major role in the regulation of movement, hormone secretion, mood and various motivational behaviors related to reward and reinforcement. While the contribution of the dopaminergic system has frequently been implicated in the etiology of alcohol/drug dependence, the mechanisms underlying this have remained unclear. It has been suggested that genetic factors might contribute individual differences in the regulation of D 2 receptor density and liability for predisposition to alcohol/drug dependence. This is supported by recent positron emission tomography (PET) studies which have consistently demonstrated that alcohol, 2,3 cocaine 4,5 and opiate 6 abusers have lower striatal D 2 receptor availability in vivo compared to healthy volunteers. The molecular basis of the possible hereditary factors in the dopaminergic system affecting predisposition to alcohol/drug dependence have remained unknown. The three nucleotide substitutions causing alteration in amino acid sequence found in the coding region of the D 2 dopamine receptor gene have been revealed to be relatively rare 9 and without clear effect on the D 2 receptor function in vivo. 10 While some regulatory sequences and promoter regions have been identified for human D 1 , 11 D 5 12 and rat D 2 13-15 receptors within the 5′ flanking region, little is known about the molecular events that regulate the transcription of the human D 2 receptor. From the several polymorphic gene markers, the A1 allele of TaqIA RFLP within the D 2 receptor gene suggests association with a specific type of alcoholism. 7 Despite numerous case-control studies, 16 the role of the A1 al...

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Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

Cited by 119 publications

References 33 publications

Molecular epidemiology of major depressive disorder

Molecular epidemiology of major depressive disorder

Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

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