ASpdb: an integrative knowledgebase of human protein isoforms from experimental and AI-predicted structures

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	Protein Summary
	AS Summary
	Protein Functional Features
	Gene Isoform Structures and Expression Levels
	Protein Structures
	pLDDT Score Distribution
	Ramachandran Plot of Protein Structures
	Potential Active Site Information
	Protein Structure and Feature Comparision
	Protein-Protein Interaction
	Related Drugs
	Related Diseases
	Clinically Important Variants

Protein:DRD2

Protein Summary

Gene summary

Gene name: DRD2
ASpdb.0 ID: 1813
	Gene
Gene symbol	DRD2
Gene ID	1813
Gene name	dopamine receptor D2
Synonyms	D2DR\|D2R
Cytomap	11q23.2
Type of gene	protein-coding
Description	D(2) dopamine receptordopamine D2 receptorseven transmembrane helix receptor
Modification date	20240411
UniProtAcc	P14416

Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Gene	DRD2	GO:0001591	dopamine neurotransmitter receptor activity, coupled via Gi/Go	8301582
Gene	DRD2	GO:0005886	plasma membrane	8413587\|26554819
Gene	DRD2	GO:0005929	cilium	28154160
Gene	DRD2	GO:0007195	adenylate cyclase-inhibiting dopamine receptor signaling pathway	8666994\|26554819
Gene	DRD2	GO:0032795	heterotrimeric G-protein binding	33571431
Gene	DRD2	GO:0034776	response to histamine	16839358
Gene	DRD2	GO:0050482	arachidonic acid secretion	8301582
Gene	DRD2	GO:0050709	negative regulation of protein secretion	16839358
Gene	DRD2	GO:0060170	ciliary membrane	20531939
Gene	DRD2	GO:0097648	G protein-coupled receptor complex	33571431
Gene	DRD2	GO:0097730	non-motile cilium	20531939
Gene	DRD2	GO:1900168	positive regulation of glial cell-derived neurotrophic factor production	23373701

AS Summary

Information of the canonical protein with experimentally identified structure from PDB (2023).

UniProt Acc	File name	PDB ID	Method	Resolution	Chain	Start	End
P14416-1	P14416-1_6cm4_A.pdb	6CM4	X-ray	2.87	A	364	442

ASpdb's canonical and alternatively spliced isoform information.

accession_id

gene_name

canonical_id

alternative_id

canonical_length

alternative_length

canonical_start

canonical_end

type

originalSEQ

variationSEQ

alternative_start

alternative_end

P14416

DRD2

P14416-1

P14416-2

443

414

242

270

Deletion

none

241

P14416

DRD2

P14416-1

P14416-3

443

445

270

Substitution

VVQ

270

272

Multiple sequence alignment of our canonical and alternatively spliced DRD2

Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of DRD2

UniProt-id	ENSG	ENST	ENSP
P14416-1	ENSG00000149295.14	ENST00000362072.8	ENSP00000354859.3
P14416-1	ENSG00000149295.14	ENST00000542968.5	ENSP00000442172.1
P14416-2	ENSG00000149295.14	ENST00000346454.7	ENSP00000278597.5
P14416-3	ENSG00000149295.14	ENST00000538967.5	ENSP00000438215.1

UniProt-id	NM ID	NP ID
P14416-1	NM_000795.3	NP_000786.1
P14416-1	XM_017017296.1	XP_016872785.1
P14416-2	NM_016574.3	NP_057658.2

Amino acid sequences of our canonical and alternatively spliced DRD2

accession_id	Protein sequence
P14416-1	MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVSREKALQTTTNYLIVSLAVADLLVATLVMPW VVYLEVVGEWKFSRIHCDIFVTLDVMMCTASILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQN ECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPLKGNCTHPEDMKLCTVIMKSNGSFPVNRRRV EAARRAQELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSR
P14416-2	MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVSREKALQTTTNYLIVSLAVADLLVATLVMPW VVYLEVVGEWKFSRIHCDIFVTLDVMMCTASILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQN ECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPLKEAARRAQELEMEMLSSTSPPERTRYSPIP PSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSRRKLSQQKEKKATQMLAIVLGVFIICWLPF
P14416-3	MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVSREKALQTTTNYLIVSLAVADLLVATLVMPW VVYLEVVGEWKFSRIHCDIFVTLDVMMCTASILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQN ECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPLKGNCTHPEDMKLCTVIMKSNGSFPVNRRRV VQEAARRAQELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTM

Protein Functional Features

Main function of this protein. (from UniProt)

DRD2 (go to UniProt):P14416

Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
P14416	Topological domain	214	373	Note=Cytoplasmic;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Deletion;Start=242;End=270
P14416	Topological domain	214	373	Note=Cytoplasmic;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Substitution;Start=270;End=270
P14416	Region	211	373	Note=Interaction with PPP1R9B;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Deletion;Start=242;End=270
P14416	Region	211	373	Note=Interaction with PPP1R9B;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Substitution;Start=270;End=270

Gene Isoform Structures and Expression Levels for DRD2

Gene structures of our canonical and alternative spliced genes of DRD2
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Expression levels of gene isoforms across GTEx.

Expression levels of gene isoforms across TCGA.

Protein Structures

PDB and CIF files of the predicted protein structures
* Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

3D view using mol* of P14416-1

3D view using mol* of P14416-2

3D view using mol* of P14416-3

pLDDT Score Distribution

pLDDT score distribution of the predicted protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

pLDDT distribution across the protein length of P14416-1

pLDDT distribution across the protein length of P14416-2

pLDDT distribution across the protein length of P14416-3

Ramachandran Plot of Protein Structures

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide.

Ramachandran plot of P14416-1

Ramachandran plot of P14416-2

Ramachandran plot of P14416-3

Potential Active Site Information

The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite.

UniProt-id	Site score	Size	D score	Volume	Exposure	Enclosure	Contact	Phobic	Philic	Balance	Don/Acc	Residues
P14416-1	1.068	176	1.128	636.265	0.565	0.71	0.922	1.188	0.73	1.628	0.798	64,65,67,69,70,73,132,135,136,139,140,142,143,209, 212,213,216,217,219,220,223,363,365,366,367,368,36 9,370,371,372,373,374,375,376,379,428,429,430,431, 432
P14416-2	1.064	214	1.114	653.072	0.565	0.723	0.898	0.839	0.797	1.053	2.001	37,40,41,44,91,94,95,98,99,100,110,111,114,115,118 ,119,181,182,183,184,185,187,190,193,194,197,357,3 60,361,364,367,368,374,376,377,379,380,381,383,384 ,387,388
P14416-3	1.064	191	1.1	635.579	0.581	0.75	0.943	0.83	0.889	0.934	2.105	33,34,37,91,94,95,98,99,100,110,111,114,115,118,11 9,122,181,182,183,184,187,190,193,194,197,388,391, 392,395,398,399,404,405,407,408,410,411,412,414,41 7,418

Protein Structure and Feature Comparision

Protein Structure Comparision Using Template Modeling Scores (TM-score).

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green)

3D view using mol* of P14416-1_P14416-1_6cm4_A.pdb

Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P14416-1_6cm4_A_P14416-2.pdb

3D view using mol* of P14416-1_6cm4_A_P14416-3.pdb

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P14416-1_P14416-2.pdb

3D view using mol* of P14416-1_P14416-3.pdb

Protein Feature Comparison of the protein sequendary structures among the protiens.

./stats/secondary_structure/figure/P14416-1_vs_P14416-2.png

./stats/secondary_structure/figure/P14416-1_vs_P14416-3.png

Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens.

./stats/relative_asa/P14416-1_vs_P14416-2.png

./stats/relative_asa/P14416-1_vs_P14416-3.png

Protein-Protein Interaction

Interactors from UniProt.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
P14416	Region	211	373	Note=Interaction with PPP1R9B;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Deletion;Start=242;End=270
P14416	Region	211	373	Note=Interaction with PPP1R9B;Ontology_term=ECO:0000250;evidence=ECO:0000250	Type=Substitution;Start=270;End=270

Interactors from STRING.

Gene name

Interactors

Related Drugs to DRD2

Drugs targeting this gene/protein.
(DrugBank)

UniProt accession	Gene name	DrugBank ID	Drug name	Drug group	Actions
P14416	DRD2	DB05766	Norclozapine	investigational
P14416	DRD2	DB00933	Mesoridazine	approved, investigational	antagonist
P14416	DRD2	DB00363	Clozapine	approved	antagonist
P14416	DRD2	DB04924	Itopride	investigational
P14416	DRD2	DB00988	Dopamine	approved	agonist
P14416	DRD2	DB01267	Paliperidone	approved	antagonist
P14416	DRD2	DB09097	Quinagolide	approved, investigational	agonist
P14416	DRD2	DB00409	Remoxipride	approved, withdrawn	antagonist
P14416	DRD2	DB00805	Minaprine	approved	agonist
P14416	DRD2	DB00413	Pramipexole	approved, investigational	agonist
P14416	DRD2	DB06148	Mianserin	approved, investigational	antagonist
P14416	DRD2	DB12093	Tetrahydropalmatine	investigational	antagonist
P14416	DRD2	DB06454	Sarizotan	investigational	partial agonist
P14416	DRD2	DB06144	Sertindole	approved, investigational, withdrawn	antagonist
P14416	DRD2	DB12061	Pardoprunox	investigational
P14416	DRD2	DB04946	Iloperidone	approved	antagonist
P14416	DRD2	DB00420	Promazine	approved, vet_approved	antagonist
P14416	DRD2	DB00502	Haloperidol	approved	antagonist
P14416	DRD2	DB00543	Amoxapine	approved	antagonist
P14416	DRD2	DB12518	Raclopride	investigational	antagonist
P14416	DRD2	DB00696	Ergotamine	approved	agonist
P14416	DRD2	DB06109	YKP-1358	investigational	antagonist
P14416	DRD2	DB09286	Pipamperone	investigational	antagonist
P14416	DRD2	DB04844	Tetrabenazine	approved, investigational	inhibitor
P14416	DRD2	DB01392	Yohimbine	approved, investigational, vet_approved	antagonist
P14416	DRD2	DB09128	Brexpiprazole	approved, investigational	partial agonist
P14416	DRD2	DB12478	Piribedil	investigational
P14416	DRD2	DB00508	Triflupromazine	approved, vet_approved	antagonist
P14416	DRD2	DB00408	Loxapine	approved	antagonist
P14416	DRD2	DB01151	Desipramine	approved, investigational	binder
P14416	DRD2	DB00831	Trifluoperazine	approved, investigational	antagonist
P14416	DRD2	DB01175	Escitalopram	approved	inhibitor
P14416	DRD2	DB00623	Fluphenazine	approved	antagonist
P14416	DRD2	DB01184	Domperidone	approved, investigational, vet_approved	antagonist
P14416	DRD2	DB01186	Pergolide	approved, investigational, vet_approved, withdrawn	agonist
P14416	DRD2	DB00391	Sulpiride	approved, investigational	antagonist
P14416	DRD2	DB04599	Aniracetam	experimental
P14416	DRD2	DB06288	Amisulpride	approved, investigational	antagonist
P14416	DRD2	DB01200	Bromocriptine	approved, investigational, withdrawn	agonist
P14416	DRD2	DB00320	Dihydroergotamine	approved, investigational	agonist
P14416	DRD2	DB01221	Ketamine	approved, vet_approved	agonist, partial agonist
P14416	DRD2	DB09018	Bromopride	investigational	antagonist
P14416	DRD2	DB04888	Bifeprunox	investigational
P14416	DRD2	DB00568	Cinnarizine	approved, investigational	other/unknown
P14416	DRD2	DB00555	Lamotrigine	approved, investigational	agonist, inhibitor
P14416	DRD2	DB01224	Quetiapine	approved	antagonist
P14416	DRD2	DB08922	Perospirone	experimental	antagonist
P14416	DRD2	DB00372	Thiethylperazine	approved, withdrawn	antagonist
P14416	DRD2	DB00248	Cabergoline	approved	agonist
P14416	DRD2	DB11274	Dihydro-alpha-ergocryptine	approved	agonist
P14416	DRD2	DB01233	Metoclopramide	approved, investigational	antagonist
P14416	DRD2	DB01235	Levodopa	approved	agonist
P14416	DRD2	DB01238	Aripiprazole	approved, investigational	antagonist, partial agonist
P14416	DRD2	DB06229	Ocaperidone	investigational
P14416	DRD2	DB04857	Brasofensine	investigational
P14416	DRD2	DB01239	Chlorprothixene	approved, experimental, investigational, withdrawn	antagonist
P14416	DRD2	DB14185	Aripiprazole lauroxil	approved, investigational	partial agonist
P14416	DRD2	DB06216	Asenapine	approved	antagonist
P14416	DRD2	DB04889	Bicifadine	investigational
P14416	DRD2	DB05271	Rotigotine	approved	agonist
P14416	DRD2	DB00777	Propiomazine	approved	antagonist
P14416	DRD2	DB00734	Risperidone	approved, investigational	antagonist
P14416	DRD2	DB01100	Pimozide	approved	antagonist
P14416	DRD2	DB00875	Flupentixol	approved, investigational, withdrawn	antagonist
P14416	DRD2	DB09194	Etoperidone	withdrawn	antagonist
P14416	DRD2	DB13025	Tiapride	investigational	blocker
P14416	DRD2	DB00458	Imipramine	approved	binder
P14416	DRD2	DB00334	Olanzapine	approved, investigational	antagonist
P14416	DRD2	DB00726	Trimipramine	approved	other/unknown
P14416	DRD2	DB00490	Buspirone	approved, investigational	antagonist
P14416	DRD2	DB00679	Thioridazine	approved, withdrawn	antagonist
P14416	DRD2	DB01614	Acepromazine	experimental, vet_approved	antagonist
P14416	DRD2	DB00714	Apomorphine	approved, investigational	agonist
P14416	DRD2	DB00433	Prochlorperazine	approved, vet_approved	antagonist
P14416	DRD2	DB01618	Molindone	approved	antagonist
P14416	DRD2	DB01621	Pipotiazine	approved, investigational	antagonist
P14416	DRD2	DB01069	Promethazine	approved, investigational	antagonist
P14416	DRD2	DB01043	Memantine	approved, investigational	antagonist, agonist
P14416	DRD2	DB09207	AS-8112	experimental	antagonist
P14416	DRD2	DB01622	Thioproperazine	experimental	antagonist
P14416	DRD2	DB01623	Thiothixene	approved	antagonist
P14416	DRD2	DB00182	Amphetamine	approved, illicit, investigational	binder
P14416	DRD2	DB01624	Zuclopenthixol	approved, investigational	antagonist
P14416	DRD2	DB00246	Ziprasidone	approved	antagonist
P14416	DRD2	DB05687	BL-1020	investigational
P14416	DRD2	DB00477	Chlorpromazine	approved, investigational, vet_approved	antagonist
P14416	DRD2	DB09224	Melperone	investigational	antagonist
P14416	DRD2	DB09223	Blonanserin	investigational	antagonist
P14416	DRD2	DB01549	Rolicyclidine	experimental, illicit
P14416	DRD2	DB04842	Fluspirilene	approved, investigational	antagonist
P14416	DRD2	DB01063	Acetophenazine	approved	antagonist
P14416	DRD2	DB01403	Methotrimeprazine	approved, investigational	antagonist
P14416	DRD2	DB01425	Alizapride	investigational	antagonist
P14416	DRD2	DB00850	Perphenazine	approved	antagonist
P14416	DRD2	DB00450	Droperidol	approved, vet_approved	antagonist
P14416	DRD2	DB06077	Lumateperone	approved, investigational	partial agonist
P14416	DRD2	DB09225	Zotepine	approved, investigational, withdrawn	antagonist
P14416	DRD2	DB00268	Ropinirole	approved, investigational	agonist
P14416	DRD2	DB08815	Lurasidone	approved, investigational	antagonist
P14416	DRD2	DB00715	Paroxetine	approved, investigational	other/unknown
P14416	DRD2	DB01038	Carphenazine	withdrawn	antagonist
P14416	DRD2	DB05964	Amitifadine	investigational
P14416	DRD2	DB00540	Nortriptyline	approved	antagonist
P14416	DRD2	DB06477	Sumanirole	investigational
P14416	DRD2	DB06016	Cariprazine	approved, investigational	partial agonist
P14416	DRD2	DB12579	JNJ-37822681	investigational	antagonist
P14416	DRD2	DB00915	Amantadine	approved	agonist
P14416	DRD2	DB00934	Maprotiline	approved, investigational	binder
P14416	DRD2	DB00589	Lisuride	approved, investigational	agonist

Related Diseases to DRD2

Previous studies relating to the alternative splicing of DRD2 and disease information from the MeSH term (PubMed)

Gene	PMID	Title	Abstract	MeSH ID	MeSH term
DRD2	9457173	Dopamine receptors: from structure to function.	The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2, D3, and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.	D006973	Hypertension
DRD2	20403997	Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer.	Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide.	D015179	Colorectal Neoplasms
DRD2	21150907	Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse.	The dopamine receptor D2 (encoded by DRD2) is implicated in susceptibility to mental disorders and cocaine abuse, but mechanisms responsible for this relationship remain uncertain. DRD2 mRNA exists in two main splice isoforms with distinct functions: D2 long (D2L) and D2 short (D2S, lacking exon 6), expressed mainly postsynaptically and presynaptically, respectively. Two intronic single-nucleotide polymorphisms (SNPs rs2283265 (intron 5) and rs1076560 (intron 6)) in high linkage disequilibrium (LD) with each other have been reported to alter D2S/D2L splicing and several behavioral traits in human subjects, such as memory processing. To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls). Robust effects of rs2283265 and rs1076560 on reducing formation of D2S relative to D2L were confirmed. The minor alleles of rs2283265/rs1076560 were considerably more frequent in Caucasians (18%) compared with African Americans (7%). Also, in Caucasians, rs2283265/rs1076560 minor alleles were significantly overrepresented in cocaine abusers compared with controls (rs2283265: 25 to 9%, respectively; p=0.001; OR=3.4 (1.7-7.1)). Several SNPs previously implicated in diverse clinical association studies are in high LD with rs2283265/rs1076560 and could have served as surrogate markers. Our results confirm the role of rs2283265/rs1076560 in D2 alternative splicing and support a strong role in susceptibility to cocaine abuse.	D019970	Cocaine-Related Disorders
DRD2	21150907	Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse.	The dopamine receptor D2 (encoded by DRD2) is implicated in susceptibility to mental disorders and cocaine abuse, but mechanisms responsible for this relationship remain uncertain. DRD2 mRNA exists in two main splice isoforms with distinct functions: D2 long (D2L) and D2 short (D2S, lacking exon 6), expressed mainly postsynaptically and presynaptically, respectively. Two intronic single-nucleotide polymorphisms (SNPs rs2283265 (intron 5) and rs1076560 (intron 6)) in high linkage disequilibrium (LD) with each other have been reported to alter D2S/D2L splicing and several behavioral traits in human subjects, such as memory processing. To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls). Robust effects of rs2283265 and rs1076560 on reducing formation of D2S relative to D2L were confirmed. The minor alleles of rs2283265/rs1076560 were considerably more frequent in Caucasians (18%) compared with African Americans (7%). Also, in Caucasians, rs2283265/rs1076560 minor alleles were significantly overrepresented in cocaine abusers compared with controls (rs2283265: 25 to 9%, respectively; p=0.001; OR=3.4 (1.7-7.1)). Several SNPs previously implicated in diverse clinical association studies are in high LD with rs2283265/rs1076560 and could have served as surrogate markers. Our results confirm the role of rs2283265/rs1076560 in D2 alternative splicing and support a strong role in susceptibility to cocaine abuse.	D020022	Genetic Predisposition to Disease

Clinically important variants in DRD2

(ClinVar, 04/20/2024)

accession_id

uniprot_id

gene_name

Type

Variant

Clinical_significance