Dopamine receptor D₁

Dopamine receptor D₁, also known as DRD1. It is one of the two types of D₁-like receptor family — receptors D₁ and D₅. It is a protein that in humans is encoded by the DRD1 gene.^[5][6][7][8]

DRD1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OZ5
Identifiers
Aliases	DRD1, dopamine receptor D1, DADR, DRD1A
External IDs	OMIM: 126449 MGI: 99578 HomoloGene: 30992 GeneCards: DRD1
Gene location (Human) Chr. Chromosome 5 (human)^[1] Band 5q35.2 Start 175,440,036 bp^[1] End 175,444,182 bp^[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)^[2] Band 13 B1|13 28.4 cM Start 54,205,202 bp^[2] End 54,209,724 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in caudate nucleus nucleus accumbens putamen prefrontal cortex Brodmann area 9 cingulate gyrus Brodmann area 46 amygdala orbitofrontal cortex middle frontal gyrus Top expressed in nucleus accumbens olfactory tubercle globus pallidus superior frontal gyrus temporal lobe amygdala urethra suprachiasmatic nucleus piriform cortex prefrontal cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function dopamine neurotransmitter receptor activity dopamine binding protein binding dopamine neurotransmitter receptor activity, coupled via Gs G protein-coupled receptor activity signal transducer activity G-protein alpha-subunit binding Cellular component membrane nucleus endoplasmic reticulum integral component of membrane plasma membrane endoplasmic reticulum membrane integral component of plasma membrane ciliary membrane endomembrane system non-motile cilium glutamatergic synapse GABA-ergic synapse integral component of postsynaptic membrane integral component of presynaptic membrane dendritic spine dendrite cell projection cilium Biological process positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway muscle contraction protein import into nucleus positive regulation of potassium ion transport response to amphetamine learning feeding behavior long-term depression temperature homeostasis striatum development prepulse inhibition response to cocaine grooming behavior behavioral response to cocaine locomotory behavior dentate gyrus development transmission of nerve impulse memory positive regulation of synaptic transmission, glutamatergic synapse assembly habituation adult walking behavior peristalsis cellular response to catecholamine stimulus adenylate cyclase-activating dopamine receptor signaling pathway regulation of dopamine uptake involved in synaptic transmission associative learning astrocyte development G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger positive regulation of release of sequestered calcium ion into cytosol mating behavior behavioral fear response activation of adenylate cyclase activity dopamine receptor signaling pathway conditioned taste aversion cerebral cortex GABAergic interneuron migration glucose import visual learning sensitization positive regulation of cell migration operant conditioning vasodilation regulation of dopamine metabolic process dopamine metabolic process phospholipase C-activating dopamine receptor signaling pathway maternal behavior dopamine transport hippocampus development neuronal action potential long-term potentiation signal transduction synaptic transmission, dopaminergic positive regulation of gene expression cellular response to dopamine regulation of protein phosphorylation G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1812 13488 Ensembl ENSG00000184845 ENSMUSG00000021478 UniProt P21728 Q61616 RefSeq (mRNA) NM_000794 NM_001291801 NM_010076 RefSeq (protein) NP_000785 NP_001278730 NP_034206 Location (UCSC) Chr 5: 175.44 – 175.44 Mb Chr 13: 54.21 – 54.21 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Tissue distribution

D₁ receptors are the most abundant kind of dopamine receptor in the central nervous system.

Northern blot and in situ hybridization show that the mRNA expression of DRD1 is highest in the dorsal striatum (caudate and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle).^[9]

Lower levels occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.^[9]

Function

D₁ receptors regulate the memory, learning, and the growth of neurons, also is used in the reward system and locomotor activity, mediating some behaviors and modulating dopamine receptor D₂-mediated events.^[10][8]

They play a role in addiction by facilitating the gene expression changes that occur in the nucleus accumbens during addiction.

They are Gs/a coupled and can stimulate neurons by indirectly activating cyclic AMP-dependent protein kinase.

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).^[11] D₁ receptor has a high degree of structural homology to another dopamine receptor, D₅, and they both bind similar drugs.^[12] As a result, none of the known orthosteric 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.^[11] Some of the benzazepines have high intrinsic activity whereas others do not. In 2015 the first positive allosteric modulator for the human D₁ receptor was discovered by high-throughput screening.^[13]

Agonists

 

Chemical structures of selective D₁ receptor agonists^[14][15]

Several D₁ receptor agonists are used clinically. These include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are preferentially D₂-like receptor agonists. Fenoldopam is a selective D₁ receptor partial agonist that does not cross the blood-brain-barrier and is used intravenously in the treatment of hypertension. Dihydrexidine and adrogolide (ABT-431) (a prodrug of A-86929 with improved bioavailability) are the only selective, centrally active D₁-like receptor agonists that have been studied clinically in humans.^[16] The selective D₁ agonists give profound antiparkinson effects in humans and primate models of PD, and yield cognitive enhancement in many preclinical models and a few clinical trials. The most dose-limiting feature is profound hypotension, but the clinical development was impeded largely by lack of oral bioavailability and short duration of action.^[16][17][18] In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D₁ agonists that are in clinical development.

List of D₁ receptor agonists

• Dihydrexidine derivatives
  • A-86929 – full agonist with 14-fold selectivity for D₁-like receptors over D₂^[11][15][19]
  • 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.^[20][21] It also showed profound antiparkinson effects in MPTP-treated primates,^[22] but caused profound hypotension in one early clinical trial in Parkinson's disease.^[11] Although dihydrexidine has significant D₂ properties, it is highly biased at D₂ receptors and was used for the first demonstration of functional selectivity^[23] with dopamine receptors.^[24][25]
  • Dinapsoline – full agonist with 5-fold selectivity for D₁-like receptors over D₂^[11]
  • Dinoxyline – full agonist with approximately equal affinity for D₁-like and D₂ receptors^[11]
  • Doxanthrine – full agonist with 168-fold selectivity for D₁-like receptors over D₂^[11]
• Benzazepine derivatives
  • SKF-81297 – 200-fold selectivity for D₁ over any other receptor^[11]
  • SKF-82958 – 57-fold selectivity for D₁ over D₂^[11]
  • SKF-38393 – very high selectivity for D₁ with negligible affinity for any other receptor^[11]
  • Clozapine – partial agonist at D₁-like receptors^[26]
  • Fenoldopam – highly selective peripheral D₁ receptor partial agonist used clinically as an antihypertensive^[11]
  • 6-Br-APB – 90-fold selectivity for D₁ over D₂^[11]
• 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^[27]
  • 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
  • A photoswitchable agonist of D₁-like receptors (azodopa^[28]) has been described that allows reversible control of dopaminergic transmission in wildtype animals.

Antagonists

Many typical and atypical antipsychotics are D₁ receptor antagonists in addition to D₂ receptor antagonists. But asenapine has shown stronger D₁ receptor affinity compared to other antipsychotics. No other D₁ receptor antagonists have been approved for clinical use. Ecopipam is a selective D₁-like receptor antagonist that has been studied clinically in humans in the treatment of a variety of conditions, including schizophrenia, cocaine abuse, obesity, pathological gambling, and Tourette's syndrome, with efficacy in some of these conditions seen. The drug produced mild-to-moderate, reversible depression and anxiety in clinical studies however and has yet to complete development for any indication.

List of D₁ receptor antagonists

• Benzazepine derivatives
  • SCH-23,390 – 100-fold selectivity for D₁ over D₅^[11]
  • Ecopipam (SCH-39,166) – a selective D₁/D₅ antagonist that was being developed as an anti-obesity medication but was discontinued^[11] However, it has showed promise in reducing stuttering and is currently in Phase 2 Trials for this purpose^[29][30]

Modulators

• DETQ – PAM^[31][32][33]
• LY-3154207 – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.^[34]

Protein–protein interactions

Dopamine receptor D₁ has been shown to interact with:

• COPG2^[35]
• COPG^[35]
• DNAJC14^[36]

Receptor oligomers

The D₁ receptor forms heteromers with the following receptors: dopamine D₂ receptor,^[37] dopamine D₃ receptor,^[37][38] histamine H₃ receptor,^[39] μ opioid receptor,^[40] NMDA receptor,^[37] and adenosine A₁ receptor.^[37]

• D₁–D₂ receptor complex^[37]
• D₁−H₃−NMDAR receptor complex – a target to prevent neurodegeneration^[41]
• D₁–D3 receptor complex^[37]
• D₁–NMDAR receptor complex^[37]
• D₁–A₁ receptor complex^[37]

Structure

Several CryoEM structures of agonists bound to the dopamine D1 receptor complexed with the stimulatory heterotrimeric Gs protein have been determined. Agonist interact with extracellular loop 2 and extracellular regions of trans-membrane helices 2, 3, 6, and 7. Interactions between catechol-based agonists and three trans-membrane serine residues including S1985.42, S1995.43, and S2025.46 function as microswitches that are essential for receptor activation.^[42]

 

Dopamine D1 CryoEM structure in complex with dopamine (PDB code: 7LJD), Dopamine D1 receptor in orange, dopamine in cyan, interactions are in green.^[43]

See also

• Dopamine receptor

References

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    Dopamine D₁ receptor hetero-oligomers
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External links

• "Dopamine Receptors: D₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors,+Dopamine+D1 at the U.S. 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.