DRD4

DRD4
Identifikatori
Aliasi	DRD4
Vanjski ID-jevi	OMIM: 126452 MGI: 94926 HomoloGene: 20215 GeneCards: DRD4
Lokacija gena (čovjek)
Hrom.	Hromosom 11 (čovjek)
Kraj	640,706 bp
Lokacija gena (miš)
Hrom.	Hromosom 7 (miš)
Kraj	140,876,377 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• signal transducer activity; • potassium channel regulator activity; • SH3 domain binding; • vezivanje identičnih proteina; • dopamine neurotransmitter receptor activity; • G protein-coupled receptor activity; • GO:0001948, GO:0016582 vezivanje za proteine; • dopamine binding; • dopamine neurotransmitter receptor activity, coupled via Gi/Go; • epinephrine binding; • norepinephrine binding; • vezivanje iona metala; • G protein-coupled serotonin receptor activity; • neurotransmitter receptor activity;
Ćelijska komponenta	• integral component of membrane; • integral component of plasma membrane; • membrana; • ćelijska membrana; • postsynapse; • glutamatergic synapse; • dendrit;
Biološki proces	• response to amphetamine; • rhythmic process; • arachidonic acid secretion; • regulation of circadian rhythm; • positive regulation of dopamine uptake involved in synaptic transmission; • GO:0072468 Transdukcija signala; • fear response; • dopamine metabolic process; • behavioral response to ethanol; • behavioral response to cocaine; • positive regulation of sodium:proton antiporter activity; • cellular calcium ion homeostasis; • positive regulation of kinase activity; • adult locomotory behavior; • inhibitory postsynaptic potential; • negative regulation of protein secretion; • socijalno ponašanje; • negative regulation of voltage-gated calcium channel activity; • regulation of dopamine metabolic process; • response to histamine; • behavioral fear response; • dopamine receptor signaling pathway; • G protein-coupled receptor signaling pathway; • adenylate cyclase-inhibiting dopamine receptor signaling pathway; • regulation of postsynaptic neurotransmitter receptor internalization; • G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; • chemical synaptic transmission; • G protein-coupled serotonin receptor signaling pathway;
	Izvori:Amigo / QuickGO
Ortolozi
	1815
	13491
	ENSG00000069696; ENSG00000276825
	ENSMUSG00000025496
	P21917
	P51436
	NM_000797
	NM_007878
	NP_000788
	NP_031904
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Dopaminski receptor D₄ je dopaminski D2-liki G-protein spregnuti receptor koji je kodiran genom DRD4 sa hromosoma 11, regija 11p15.5.^[5]

Nedavno je objavljena struktura DRD4 u kombinaciji s antipsihotskim lijekom nemonaprid.^[6]

Kao i kod drugih podtipova dopaminskih receptora, receptor D₄ aktivira neurotransmiter dopamin. Povezan je s mnogim neurvnim i psihijatrijskim stanjima ^[7] uključujući shizofreniju i bipolarni poremećaj,^[8] ADHD,^[9]^[10] addiktivna ponašanja,^[11] Parkinsnsonovu bolest,^[12] i poremećaj ishrane kao što je anoreksija nervoza.^[13] Nađena je slaba povezanost između DRD4 i graničnog poremećaja ličnosti.

Također je meta lijekova koji liječe shizofreniju i Parkinsonovu bolest.^[14] Receptor D₄ smatra se sličnim D₂, u kojem aktivirani receptor inhibira enzim adenilat-ciklaza, čime se smanjuje unutarćelijska koncentracija drugog glasnika cAMPa.^[15]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 467 aminokiselina, a molekulska težina 48.361 Da.^[16].

10	20	30	40	50
MGNRSTADAD	GLLAGRGPAA	GASAGASAGL	AGQGAAALVG	GVLLIGAVLA
GNSLVCVSVA	TERALQTPTN	SFIVSLAAAD	LLLALLVLPL	FVYSEVQGGA
WLLSPRLCDA	LMAMDVMLCT	ASIFNLCAIS	VDRFVAVAVP	LRYNRQGGSR
RQLLLIGATW	LLSAAVAAPV	LCGLNDVRGR	DPAVCRLEDR	DYVVYSSVCS
FFLPCPLMLL	LYWATFRGLQ	RWEVARRAKL	HGRAPRRPSG	PGPPSPTPPA
PRLPQDPCGP	DCAPPAPGLP	RGPCGPDCAP	AAPGLPPDPC	GPDCAPPAPG
LPQDPCGPDC	APPAPGLPRG	PCGPDCAPPA	PGLPQDPCGP	DCAPPAPGLP
PDPCGSNCAP	PDAVRAAALP	PQTPPQTRRR	RRAKITGRER	KAMRVLPVVV
GAFLLCWTPF	FVVHITQALC	PACSVPPRLV	SAVTWLGYVN	SALNPVIYTV
FNAEFRNVFR	KALRACC

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

Genetika

Ljudski protein je kodiran DRD4 na hromosom 11 nalazi sw na sekvenci u 11p15,5.^[17]

Postoje male varijacije (mutacije/polimorfizmi) u ljudskom genu:

48-bazni par VNTR u egzon 3
C-521T u promotoru
Delecija 13 baznih parova, od 235 do 247 u egzonu 1
Ponavljanje 12 baznih parova u egzonu 1^[18]
Val194Gly
Polimorfna tandemska duplikacija 48 bp^[19]

Mutacije u ovom genu povezane su s različitim fenotipovima ponašanja, uključujući disfunkciju autonomnog nervnog sistema, poremećaj pažnje/hiperaktivnosti,^[20] shizofreniju^[21] and the personality trait of novelty seeking.^[22]

Također pogledajte

Dopaminska hipoteza psihoze

Reference

^ ^a ^b ^c ENSG00000276825 GRCh38: Ensembl release 89: ENSG00000069696, ENSG00000276825 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000025496 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (april 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature. 350 (6319): 610–4. Bibcode:1991Natur.350..610V. doi:10.1038/350610a0. PMID 1840645. S2CID 4244670.
^ Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL (oktobar 2017). "D4 dopamine receptor high-resolution structures enable the discovery of selective agonists". Science. 358 (6361): 381–386. Bibcode:2017Sci...358..381W. doi:10.1126/science.aan5468. PMC 5856174. PMID 29051383.
^ Ptácek R, Kuzelová H, Stefano GB (septembar 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor. 17 (9): RA215–20. doi:10.12659/MSM.881925. PMC 3560519. PMID 21873960.
^ Domschke K (juli 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin. 39 (4): 766–75. doi:10.1093/schbul/sbt040. PMC 3686457. PMID 23512949.
^ LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (maj 1996). "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder". Molecular Psychiatry. 1 (2): 121–4. PMID 9118321.
^ Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF (septembar 1998). "Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder". Molecular Psychiatry. 3 (5): 427–30. doi:10.1038/sj.mp.4000457. PMID 9774776.
^ McGeary J (septembar 2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology Biochemistry and Behavior. 93 (3): 222–9. doi:10.1016/j.pbb.2009.03.010. PMC 2706302. PMID 19336242.
^ Cormier F, Muellner J, Corvol JC (april 2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission. 120 (4): 665–71. doi:10.1007/s00702-012-0934-4. PMID 23232665. S2CID 21967333.
^ Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB (mart 2010). "Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake". Brain Research Reviews. 62 (2): 147–64. doi:10.1016/j.brainresrev.2009.10.007. PMID 19931559. S2CID 37635456.
^ Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM (april 2013). "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets. 14 (4): 507–12. doi:10.2174/1389450111314040012. PMID 23469923.
^ Neve KA, Seamans JK, Trantham-Davidson H (august 2004). "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research. 24 (3): 165–205. CiteSeerX 10.1.1.465.5011. doi:10.1081/RRS-200029981. PMID 15521361. S2CID 12407397.
^ "UniProt, P21917". Pristupljeno 21. 8. 2021.
^ Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (juli 1992). "Multiple dopamine D4 receptor variants in the human population". Nature. 358 (6382): 149–52. Bibcode:1992Natur.358..149T. doi:10.1038/358149a0. PMID 1319557. S2CID 4345839.
^ Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (oktobar 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biological Psychiatry. 34 (7): 459–64. doi:10.1016/0006-3223(93)90236-7. PMID 8268330. S2CID 34841647.
^ Rondou P, Haegeman G, Van Craenenbroeck K (juni 2010). "The dopamine D4 receptor: biochemical and signalling properties". Cellular and Molecular Life Sciences. 67 (12): 1971–86. doi:10.1007/s00018-010-0293-y. PMID 20165900. S2CID 21432517.
^ Thapar A, Langley K, Owen MJ, O'Donovan MC (decembar 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine. 37 (12): 1681–92. doi:10.1017/S0033291707000773. PMID 17506925.
^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 Arhivirano 21. 2. 2009. na Wayback Machine – SzGene database at Schizophrenia Research Forum.
^ Munafò MR, Yalcin B, Willis-Owen SA, Flint J (januar 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry. 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217. S2CID 28997438.

Vanjski linkovi

"Dopamine Receptors: D₄". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano s originala, 5. 3. 2012. Pristupljeno 21. 8. 2021.
Current Research on the DRD₄ Gene
Receptors, Dopamine D4 na US National Library of Medicine Medical Subject Headings (MeSH)
Marisa Wilson. "Are you a thrill seeker??". Davidson College. Pristupljeno 5. 4. 2008.
"The D4DR Gene". D4DR Club. Arhivirano s originala, 13. 10. 2007. Pristupljeno 5. 4. 2008.
P21917

[refGRCh38Ensembl-1] ENSG00000276825 GRCh38: Ensembl release 89: ENSG00000069696, ENSG00000276825 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000025496 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid1840645-5] Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (april 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature. 350 (6319): 610–4. Bibcode:1991Natur.350..610V. doi:10.1038/350610a0. PMID 1840645. S2CID 4244670.

[6] Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL (oktobar 2017). "D4 dopamine receptor high-resolution structures enable the discovery of selective agonists". Science. 358 (6361): 381–386. Bibcode:2017Sci...358..381W. doi:10.1126/science.aan5468. PMC 5856174. PMID 29051383.

[7] Ptácek R, Kuzelová H, Stefano GB (septembar 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor. 17 (9): RA215–20. doi:10.12659/MSM.881925. PMC 3560519. PMID 21873960.

[8] Domschke K (juli 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin. 39 (4): 766–75. doi:10.1093/schbul/sbt040. PMC 3686457. PMID 23512949.

[9] LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (maj 1996). "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder". Molecular Psychiatry. 1 (2): 121–4. PMID 9118321.

[10] Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF (septembar 1998). "Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder". Molecular Psychiatry. 3 (5): 427–30. doi:10.1038/sj.mp.4000457. PMID 9774776.

[11] McGeary J (septembar 2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology Biochemistry and Behavior. 93 (3): 222–9. doi:10.1016/j.pbb.2009.03.010. PMC 2706302. PMID 19336242.

[12] Cormier F, Muellner J, Corvol JC (april 2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission. 120 (4): 665–71. doi:10.1007/s00702-012-0934-4. PMID 23232665. S2CID 21967333.

[13] Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB (mart 2010). "Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake". Brain Research Reviews. 62 (2): 147–64. doi:10.1016/j.brainresrev.2009.10.007. PMID 19931559. S2CID 37635456.

[14] Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM (april 2013). "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets. 14 (4): 507–12. doi:10.2174/1389450111314040012. PMID 23469923.

[pmid15521361-15] Neve KA, Seamans JK, Trantham-Davidson H (august 2004). "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research. 24 (3): 165–205. CiteSeerX 10.1.1.465.5011. doi:10.1081/RRS-200029981. PMID 15521361. S2CID 12407397.

[UniProt-16] "UniProt, P21917". Pristupljeno 21. 8. 2021.

[Van_Tol_1992-17] Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (juli 1992). "Multiple dopamine D4 receptor variants in the human population". Nature. 358 (6382): 149–52. Bibcode:1992Natur.358..149T. doi:10.1038/358149a0. PMID 1319557. S2CID 4345839.

[pmid8268330-18] Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (oktobar 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biological Psychiatry. 34 (7): 459–64. doi:10.1016/0006-3223(93)90236-7. PMID 8268330. S2CID 34841647.

[19] Rondou P, Haegeman G, Van Craenenbroeck K (juni 2010). "The dopamine D4 receptor: biochemical and signalling properties". Cellular and Molecular Life Sciences. 67 (12): 1971–86. doi:10.1007/s00018-010-0293-y. PMID 20165900. S2CID 21432517.

[pmid17506925-20] Thapar A, Langley K, Owen MJ, O'Donovan MC (decembar 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine. 37 (12): 1681–92. doi:10.1017/S0033291707000773. PMID 17506925.

[SZGeneD4-21] Gene Overview of All Published Schizophrenia-Association Studies for DRD4 Arhivirano 21. 2. 2009. na Wayback Machine – SzGene database at Schizophrenia Research Forum.

[pmid17574217-22] Munafò MR, Yalcin B, Willis-Owen SA, Flint J (januar 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry. 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217. S2CID 28997438.

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