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The Dopamine Receptor D2 Drd2 Gene Biology Essay

This gene codes for D2 subtype of the dopamine receptor. It is G-protein coupled receptor that inhibits adenylyl cyclase activity. A missence mutation in this gene is associated with myoclonus dystonia; other mutations have been linked with schizophrenia. Alternative splicing of this gene results in two transcript variants coding for different isoforms. A third variant has been described but it has not been determined whether this isoform is normal or because of abnormal splicing [4]. It is one of the five dopamine receptors (D1 to D5), placed primarily in the caudate putamen, nucleus accumbens and olfactory tubercle where they participate in the regulation of locomotion, reward, reinforcement, memory and learning. It is a catecholamine neurotransmitter in the central nervous system. It shows high expression in both pituitary gland and the central nervous system. It belongs to family of G-protein coupled receptors which are associated with inhibitory functions [7].

1.2 Table

Sl. No.

E.C. No. / CATEGORY

CHROMOSOMAL LOCATION

SUBCELLULAR LOCALIZATION

FAMILY

1 [6]

Receptor membrane G [6]

11q23.2 [6]

Plasma membrane [6]

G-protein coupled receptor 1 family [6]

Structure

The DRD2 DNA is of 65.68 kb comprised of 8 exons [6]. The protein:

Fig-1: DRD2 protein structure - A Structural Basis for Nucleotide Exchange on G-alpha-i Subunits and Receptor Coupling Specificity [8].

For further details about the protein the following link can be referred: http://www.uniprot.org/uniprot/P14416

For gene: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=DetailsSearch&Term=1813[uid]

Function

It mediates its activity via G proteins which inhibit adenylyl cyclase. It is one of the five (D1 to D5) dopamine receptors [4]. It controls a variety of functions including cognition, emotion, locomotor activity, food intake and endocrine system regulation. In the periphery, dopamine modulates cardiovascular and renal function, hormone secretion, and gastrointestinal motility. Dysregulation of dopaminergic signal transmission results in various pathological conditions like Parkinson’s disease, schizophrenia, restless leg syndrome and endocrine tumours. It belongs to family of G-protein coupled receptors which are associated with inhibitory functions [7].

Signalling

Nicotine

NARs

Neurons

NAc

DRD2

Dopamine

Fig-2: DRD2 signalling [9].

Within the mesolimbic dopamine (DA) pathway nicotine stimulates nicotinic acetylcholine receptors (NARs) on neurons of the ventral tegmental area that project to the nucleus accumbens (NAc) and release DA which leads to positive reinforcement. DRD2 which is a presynaptic and postsynaptic receptor can be activated indirectly by even low concentrations of nicotine [9].

Mechanism

Higher prevalence of DRD2 TaqIA1 allele in smokers was observed compared to non-smokers. TaqIA1 allele was found to be associated with decreased D2 receptor availability in the striatum. The hypothesis that the DRD2 TaqIA1 allele would increase smoking risk by reducing the dopaminergic function was also supported in this study. This stydy strengthens the potential association between DRD2 snd smoking risks. The TaaqIA polymorphism of the DRD2 gene is represented by the SNP: dbSNP ID rs1800497 [1]. A1 allele of DRD2 gene was found to be present in smokers at high frequency as compared to non-smokers. A1 allele is linked with decreased D2 receptor density. TaqIA polymorphism had a strong relation with DRD2 gene; however studies are conflicting in relation to smoking. This study established non-association between DRD2 genotype and smoking. High frequency A2 allele was found in ever smokers than in never smokers. A1 allele carriers achieved longer abstinence periods while quitting smoking compared to non carriers. Combinational genotypes: A1+/9+ combinations had lowest association with heavy smoking as they might have high level of extracellular dopamine protecting them from heavier smoking. A1-/9- genotype combination had higher risk of regular smoking commencement before 20 years of age when compared to A1+/9+ genotype combination [2]. The TaqIA polymorphism is placed 10 KB 3’ to the final exon of the DRD2 gene itself. There are two alleles commonly referred as A1 and A2. It was recently found that TaqIA polymorphism is situated within the coding region of a kinase gene which was named ankyrin repeat and kinase domain containing 1 (ANKK1), whose function is still unknown. As such, associations between TaqIA polymorphism and DRD2 variation receptor expression are most likely because of linkage disequilibrium with functional variation of DRD2 gene still undetermined. The mechanism is still unknown. Presence of A1 allele (in the homozygous A1A1 genotype or the heterozygous A1A2 genotype, referred collectively as the A1+ genotype) is linked with decreased DRD2 receptor expression and availability in striatum relative to homozygous A2A2 (A1-) genotype. Again not all laboratories report this linkage. A1+ genotype was linked with higher nicotine addiction [3]. The rs1800497 SNP i.e. the TaqIA (or Taq1A) polymorphism of the dopamine D2 receptor DRD2 gene (located 10000 bp downstream of the gene) generates DRD2*A1 allele, which is associated with decreased number of dopamine binding sites in brain, was postulated to have a role in smoking behaviour. This less amount of dopamine binding sites was supposed to be associated with under stimulated state which can be relieved by smoking thus it might have a role in nicotine addiction. However studies associated with rs18004907 SNP and smoking behaviour are still conflicting [5], for further details about this SNP the following links can be refereed:

http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs1800497

http://www.snpedia.com/index.php/Rs1800497


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