Dopamine receptor D1

Dopamine receptor D1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1OZ5​
Identifiers
Symbols	DRD1 ; DADR; DRD1A
External IDs	OMIM: 126449 MGI: 99578 HomoloGene: 30992 IUPHAR: 214 ChEMBL: 2056 GeneCards: DRD1 Gene
Gene ontology Molecular function • dopamine neurotransmitter receptor activity, coupled via Gs • G-protein alpha-subunit binding • dopamine neurotransmitter receptor activity • protein binding • drug binding • G-protein coupled amine receptor activity • protein phosphatase binding • angiotensin receptor binding • D3 dopamine receptor binding • protein complex binding • dopamine binding • protein heterodimerization activity • ATPase binding Cellular component • nucleus • endoplasmic reticulum membrane • cytosol • plasma membrane • integral component of plasma membrane • caveola • nonmotile primary cilium • neuronal cell body • dendritic shaft • axon terminus • dendritic spine neck • dendritic spine head • ciliary membrane Biological process • temperature homeostasis • conditioned taste aversion • behavioral fear response • synaptic transmission, dopaminergic • response to amphetamine • negative regulation of protein kinase activity • protein import into nucleus • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • adenylate cyclase-activating G-protein coupled receptor signaling pathway • activation of adenylate cyclase activity • adenylate cyclase-activating dopamine receptor signaling pathway • synapse assembly • sensory perception of chemical stimulus • learning • memory • mating behavior • grooming behavior • adult walking behavior • visual learning • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • astrocyte development • response to activity • dopamine transport • transmission of nerve impulse • neuronal action potential • regulation of vasoconstriction • calcium-mediated signaling • dentate gyrus development • striatum development • orbitofrontal cortex development • cerebral cortex GABAergic interneuron migration • positive regulation of cell migration • negative regulation of cell migration • peristalsis • positive regulation of cAMP biosynthetic process • response to food • response to estradiol • response to retinoic acid • cellular response to insulin stimulus • response to nicotine • operant conditioning • social behavior • response to antidepressant • regulation of dopamine metabolic process • vasodilation • negative regulation of circadian sleep/wake cycle, sleep • dopamine metabolic process • response to drug • maternal behavior • response to amino acid • positive regulation of potassium ion transport • response to morphine • response to ethanol • positive regulation of membrane potential • glucose import • habituation • sensitization • behavioral response to cocaine • regulation of long-term neuronal synaptic plasticity • positive regulation of release of sequestered calcium ion into cytosol • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • regulation of dopamine uptake involved in synaptic transmission • positive regulation of synaptic transmission, glutamatergic • prepulse inhibition • phospholipase C-activating dopamine receptor signaling pathway • long-term synaptic potentiation • long term synaptic depression • cellular response to hypoxia • cellular response to catecholamine stimulus • positive regulation of long-term synaptic potentiation • positive regulation of feeding behavior Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1812	13488
Ensembl	ENSG00000184845	ENSMUSG00000021478
UniProt	P21728	Q61616
RefSeq (mRNA)	NM_000794	NM_001291801
RefSeq (protein)	NP_000785	NP_001278730
Location (UCSC)	Chr 5: 175.44 – 175.44 Mb	Chr 13: 54.05 – 54.06 Mb
PubMed search

Dopamine receptor D₁, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.^[1][2][3]

Function

This gene encodes the D₁ subtype of the dopamine receptor. The D₁ subtype is the most abundant dopamine receptor in the central nervous system. This G protein-coupled receptor stimulates adenylate cyclase and indirectly activates cyclic AMP-dependent protein kinases. D₁ receptors regulate neuronal growth and development, mediate some behavioral responses, and modulate dopamine receptor D₂-mediated events.^[4] Alternative transcription initiation sites result in two transcript variants of this gene.^[5]

Production

The DRD1 gene expresses primarily in the caudate putamen in humans, and in the caudate putamen, the nucleus accumbens and the olfactory tubercle in mouse. Gene expression patterns from the Allen Brain Atlases in mouse and human can be found here.

Ligands

There are a number of ligands selective for the D₁ receptors. To date, most of the known ligands are based on dihydrexidine or the prototypical benzazepine partial agonist SKF-38393 (one derivative being the prototypical antagonist SCH-23390).^[6] D₁ receptor has a high degree of structural homologine to another dopamine receptor, D₅, and they both bind similar drugs.^[7] As a result, none of the known ligands is selective for the D₁ vs. the D₅ receptor, but the benzazepines generally are more selective for the D₁ and D₅ receptors versus the D₂-like family.^[6] Some of the benzazepines have high intrinsic activity whereas others do not.

Agonists

Chemical structures of selective D₁ receptor agonists.^[8][9]

• Dihydrexidine derivatives
  • A-86929 - full agonist with 14-fold selectivity for D₁-like receptors over D₂^[6][9][10]
  • Dihydrexidine - full agonist with 10-fold selectivity for D₁-like receptors over D₂ that has been in Phase IIa clinical trials as a cognitive enhancer.^[11][12] It also showed profound antiparkinson effects in MPTP-treated primates,^[13] but caused profound hypotension in one early clinical trial in Parkinson's disease.^[6] Although dihydrexidine has significant D₂ properties, it is highly biased at D₂ receptors and was used for the first demonstration of functional selectivity^[14] with dopamine receptors.^[15][16]
  • Dinapsoline - full agonist with 5-fold selectivity for D₁-like receptors over D₂^[6]
  • Dinoxyline - full agonist with approximately equal affinity for D₁-like and D₂ receptors^[6]
  • Doxanthrine - full agonist with 168-fold selectivity for D₁-like receptors over D₂^[6]
• Benzazepine derivatives
  • SKF-81297 - 200-fold selectivity for D₁ over any other receptor^[6]
  • SKF-82958 - 57-fold selectivity for D₁ over D₂^[6]
  • SKF-38393 - very high selectivity for D₁ with negligible affinity for any other receptor^[6]
  • Fenoldopam - highly selective peripheral D₁ receptor partial agonist used clinically as an antihypertensive^[6]
  • 6-Br-APB - 90-fold selectivity for D₁ over D₂^[6]
• Others
  • Stepholidine - alkaloid with D1 agonist and D2 antagonist properties, showing antipsychotic effects
  • A-68930
  • A-77636
  • CY-208,243 - high intrinsic activity partial agonist with moderate selectivity for D₁-like over D₂-like receptors, member of ergoline ligand family like pergolide and bromocriptine.
  • SKF-89145
  • SKF-89626
  • 7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline: extremely potent, high-affinity full agonist^[17]
  • Cabergoline - weak D₁ agonism, highly selective for D₂, and various serotonin receptors
  • Pergolide - (similar to cabergoline) weak D₁ agonism, highly selective for D₂, and various serotonin receptors

Antagonists

• Benzazepine derivatives
  • SCH-23,390 - 100-fold selectivity for D₁ over D₅^[6]
  • SKF-83,959 - 7-fold selectivity for D₁ over D₅ with negligible affinity for other receptors;^[6] acts as an antagonist at D₁ but as an agonist at D₅
  • Ecopipam (SCH-39,166) - a selective D₁/D₅ antagonist that was being developed as an anti-obesity medication but was discontinued^[6]

Protein-protein interactions

Dopamine receptor D₁ has been shown to interact with:

• COPG2,^[18]
• COPG,^[18] and
• DNAJC14.^[19]

Receptor oligomers

The D₁ receptor forms heteromers with the following receptors: dopamine D₂, D₃,^[20] histamine H₃,^[21] μ opioid.^[22]

See also

• Dopamine receptor

References

1. Dearry A, Gingrich JA, Falardeau P, Fremeau RT, Bates MD, Caron MG (September 1990). "Molecular cloning and expression of the gene for a human D₁ dopamine receptor". Nature 347 (6288): 72–6. doi:10.1038/347072a0. PMID 2144334.
2. Zhou QY, Grandy DK, Thambi L, Kushner JA, Van Tol HH, Cone R, Pribnow D, Salon J, Bunzow JR, Civelli O (September 1990). "Cloning and expression of human and rat D₁dopamine receptors". Nature 347 (6288): 76–80. doi:10.1038/347076a0. PMID 2168520.
3. Sunahara RK, Niznik HB, Weiner DM, Stormann TM, Brann MR, Kennedy JL, Gelernter JE, Rozmahel R, Yang YL, Israel Y (September 1990). "Human dopamine D₁ receptor encoded by an intronless gene on chromosome 5". Nature 347 (6288): 80–3. doi:10.1038/347080a0. PMID 1975640.
4. ML Paul, AM Graybiel, JC David, HA Robertson (1992). "D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease". The Journal of Neuroscience 12 (10): 3729–3742.
5. "Entrez Gene: DRD1 dopamine receptor D₁".
6. Zhang J, Xiong B, Zhen X, Zhang A (2009). "Dopamine D₁ receptor ligands: where are we now and where are we going.". Med Res Rev. 29 (2): 272–294. doi:10.1002/med.20130. PMID 18642350.
7. Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991). "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1". Nature 350 (6319): 614–9. doi:10.1038/350614a0. PMID 1826762.
8. Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (November 2006). "trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist". J. Med. Chem. 49 (23): 6848–57. doi:10.1021/jm0604979. PMID 17154515.
9. Michaelides MR, Hong Y, DiDomenico S, Asin KE, Britton DR, Lin CW, Williams M, Shiosaki K (1995). "(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1- ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D₁agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)". J. Med. Chem. 38 (18): 3445–7. doi:10.1021/jm00018a002. PMID 7658429.
10. Yamashita M, Yamada K, Tomioka K (2004). "Construction of arene-fused-piperidine motifs by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric synthesis of a dopamine D₁ full agonist, A-86929". J. Am. Chem. Soc. 126 (7): 1954–5. doi:10.1021/ja031760n. PMID 14971926.
11. Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, Nahas Z, Kozel FA, Kose S, Knable M, Fernandes P, Nichols DE, Mailman RB, George MS (2007). "A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia.". Schizophr Res. 94 (1-3): 332–341. doi:10.1016/j.schres.2007.03.033. PMID 17596915.
12. George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K, Nahas Z, Knable M, Fernandes P, Juncos J, Huang X, Nichols DE, Mailman RB (2007). "A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia.". Schizophr Res. 93 (1-3): 42–50. doi:10.1016/j.schres.2007.03.011. PMID 17467956.
13. Taylor JR, Lawrence MS, Redmond DE, Elsworth JD, Roth RH, Nichols DE, Mailman RB (1991). "Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in monkeys.". Eur J Pharmacol. 199 (3): 389–391. doi:10.1016/0014-2999(91)90508-N. PMID 1680717.
14. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (January 2007). "Functional selectivity and classical concepts of quantitative pharmacology". J. Pharmacol. Exp. Ther. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID 16803859.
15. Mottola DM, Kilts JD, Lewis MM, Connery HS, Walker QD, Jones SR, Booth RG, Hyslop DK, Piercey M, Wightman RM, Lawler CP, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase". J. Pharmacol. Exp. Ther. 301 (3): 1166–78. doi:10.1124/jpet.301.3.1166. PMID 12023552.
16. Kilts JD, Connery HS, Arrington EG, Lewis MM, Lawler CP, Oxford GS, O'Malley KL, Todd RD, Blake BL, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs". J. Pharmacol. Exp. Ther. 301 (3): 1179–89. doi:10.1124/jpet.301.3.1179. PMID 12023553.
17. Bonner LA, Chemel BR, Watts VJ, Nichols DE (September 2010). "Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists". Bioorg. Med. Chem. 18 (18): 6763–70. doi:10.1016/j.bmc.2010.07.052. PMC 2941879. PMID 20709559.
18. Bermak JC, Li M, Bullock C, Weingarten P, Zhou QY (Feb 2002). "Interaction of gamma-COP with a transport motif in the D1 receptor C-terminus". Eur. J. Cell Biol. 81 (2): 77–85. doi:10.1078/0171-9335-00222. PMID 11893085.
19. Bermak JC, Li M, Bullock C, Zhou QY (May 2001). "Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein". Nat. Cell Biol. 3 (5): 492–8. doi:10.1038/35074561. PMID 11331877.
20. Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark H, Soriano A, Barnes C, Goldberg SR, Lluis C, Fuxe K, Franco R (2008). "Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum". J. Biol. Chem. 283 (38): 26016–25. doi:10.1074/jbc.M710349200. PMC 2533781. PMID 18644790.
21. Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré S, Lluís C, Franco R (2009). "Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors". Br. J. Pharmacol. 157 (1): 64–75. doi:10.1111/j.1476-5381.2009.00152.x. PMC 2697789. PMID 19413572.
22. Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O'Dowd BF (2008). "Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells". Eur. J. Pharmacol. 581 (3): 235–43. doi:10.1016/j.ejphar.2007.11.060. PMID 18237729.

External links

• "Dopamine Receptors: D₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors, Dopamine D1 at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.