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Dopamine receptor D5
Dopamine receptor D5
Dopamine receptor D5
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DRD5
Identifiers
AliasesDRD5, DBDR, DRD1B, DRD1L2, dopamine receptor D5
External IDsOMIM: 126453; MGI: 94927; HomoloGene: 20216; GeneCards: DRD5; OMA:DRD5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1816

13492

Ensembl

ENSG00000169676

ENSMUSG00000039358

UniProt

P21918

Q8BLD9

RefSeq (mRNA)

NM_000798

NM_013503

RefSeq (protein)

NP_000789

NP_038531

Location (UCSC)Chr 4: 9.78 – 9.78 MbChr 5: 38.48 – 38.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Dopamine receptor D5, also known as D1BR, is a protein that in humans is encoded by the DRD5 gene.[5] It belongs to the D1-like receptor family along with the D1 receptor subtype.

Function

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D5 receptor is a subtype of the dopamine receptor that has a 10-fold higher affinity for dopamine than the D1 subtype.[6] The D5 subtype is a G-protein coupled receptor, which promotes synthesis of cAMP by adenylyl cyclase via activation of Gαs/olf family of G proteins.[7][8] Both D5 and D1 subtypes activate adenylyl cyclase. D1 receptors were shown to stimulate monophasic dose-dependent accumulation of cAMP in response to dopamine, and the D5 receptors were able to stimulate biphasic accumulation of cAMP under the same conditions, suggesting that D5 receptors may use a different system of secondary messengers than D1 receptors.[9]

Activation of D5 receptors is shown to promote expression of brain-derived neurotrophic factor and increase phosphorylation of protein kinase B in rat and mice prefrontal cortex neurons.[10]

In vitro, D5 receptors show high constitutive activity that is independent of binding any agonists.[11]

Primary structure

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D5 receptor is highly homologous to the D1 receptor. Their amino acid sequences are 49%[6] to 80%[12] identical. D5 receptor has a long C-terminus of 93 amino acids, accounting for 26% of the entire protein. In spite of the high degree of homology between D5 and D1 receptors, their c-terminus tails have little similarity.[12]

Chromosomal location

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In humans, D5 receptor is encoded on the chromosome 4p15.1–p15.3.[13] The gene lacks introns[9] and encodes a product of 477 amino acids.[6] Two pseudogenes for D5 receptor exist that share 98% sequence with each other and 95% sequence with the functional DRD5 gene. These genes contain several in-frame stop codons that prevent these genes from transcribing a functional protein.[9]

Expression

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Central nervous system

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D5 receptor is expressed more widely in the CNS than its close structural homolog dopamine receptor D1.[14] It is found in neurons in amygdala, frontal cortex, hippocampus, striatum, thalamus, hypothalamus, basal forebrain, cerebellum,[14] and midbrain.[15] Dopamine receptor D5 is exclusively expressed by large aspiny neurons in neostriatum of primates, which are typically cholinergic interneurons.[16] Within a cell, D5 receptors are found on the membrane of soma and proximal dendrites.[14] They are also sometimes located in the neuropil in the olfactory region, superior colliculus, and cerebellum.[14] D5 receptor is also found in striatal astrocytes of the rat basal ganglia.[17]

The receptors of this subtype are also expressed on dendritic cells and T helper cells.[18]

Kidney

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D5 receptors are expressed in kidneys and are involved in regulation of sodium excretion. They are located on proximal convoluted tubules, and their activation suppresses the activity of sodium–hydrogen antiporter and Na+/K+-ATPase, preventing reabsorption of sodium.[19] D5 receptors are thought to positively regulate expression of renalase.[20] Their faulty functioning in nephrons can contribute to hypertension.[19][20]

Clinical significance

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Learning and memory

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D5 receptor participates in the synaptic processes that underlie learning and memory. These receptors participate in the formation of LTD in rodent striatum, which is opposite to the D1 receptor involvement with the formation of LTP in the same brain region.[21] D5 receptors are also associated with the consolidation of fear memories in amygdala. It has been shown that M1-Muscarinic receptors cooperate with D5 receptors and beta-2 adrenergic receptors to consolidate cued fear memory. It is suggested that these G protein-coupled receptors redundantly activate phospholipase C in basolateral amygdala. One effect of the activation of phospholipase C is deactivation of KCNQ channels.[22] Since KCNQ channels conduct M current that raises the threshold for action potential,[23] deactivation of these channels leads to increased neuronal excitability and enhanced memory consolidation.[22]

D5 receptors may be required for long-term potentiation at the synapse between medial perforant path and dentate gyrus in murine hippocampal formation.[24]

Addiction

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Smoking

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Polymorphisms in the DRD5 gene, which encodes dopamine receptor D5, have been suggested to play a role in the initiation of smoking. In a study on the association of four polymorphisms of this gene with smoking, a statistical analysis suggested that there may exist a haplotype of DRD5 that is protective against initiation of smoking.[25]

ADHD

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Dinucleotide repeats of DRD5 gene are associated with ADHD in humans. 136-bp allele of the gene was shown to be a protective factor against developing this disorder, and 148-bp allele of DRD5 was shown to be a risk factor for it.[14] There exist two types of the 148-bp allele of DRD5, a long and a short one. The short dinucleotide repeat allele is associated with ADHD, but not the long one.[26] Another allele of DRD5 that is moderately associated with ADHD susceptibility is 150 bp.[27] In a rat model of ADHD, low density of D5 was found in the hippocampal pyramidal cell somas. Deficiency in D5 receptors may contribute to learning problems that may be associated with ADHD.[28]

Parkinson's disease

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D5 receptors may be involved in burst firing of subthalamic nucleus neurons in 6-OHDA rat model of Parkinson's disease. In this animal model, blockage of D5 receptors with flupentixol reduces burst firing and improves motor deficits.[29] Studies show that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations or hallucinations in PD.[30][31]

Schizophrenia

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Several polymorphisms in DRD5 genes have been associated with susceptibility to schizophrenia. The 148 bp allele of DRD5 was linked to increased risk of schizophrenia.[32] Some single-nucleotide polymorphisms in this gene, including changes in rs77434921, rs1800762, rs77434921, and rs1800762, in northern Han Chinese population.[33]

Locomotion

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D5 receptor is believed to participate in modulation of psychostimulant-induced locomotion. Mice lacking D5 receptors show increased motor response to administration of methamphetamine than wild type mice,[34] which suggests that these receptors have a role in controlling motor activity.

Regulation of blood pressure

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D5 receptor may be involved in modulation of the neuronal pathways that regulate blood pressure. Mice lacking this receptor in their brains showed hypertension and elevated blood pressure, which may have been caused by increased sympathetic tone.[35] D5 receptors that are expressed in kidneys are also involved in the regulation of blood pressure via modulating expression of renalase and excretion of sodium, and disturbance of these processes can contribute to hypertension as well.[20]

Immunity

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D5 receptors negatively regulate production of IFNγ by NK cells. The expression of D5 receptors was shown to be upregulated in NK cells in response to prolonged stimulation with recombinant interleukin 2. This upregulation inhibits proliferation of the NK cells and suppresses synthesis of IFNγ. Activation of D5 prevents p50, part of NF-κB protein complex, from repressing the transcription of miRNA 29a. Because miRNA29a targets mRNA of IFNγ, the expression of IFNγ protein is diminished.[36]

D5 receptors are involved in activation and differentiation of T helper 17 cells. Specifically, these receptors play a role in polarization of CD4+ T-cells into the T helper 17 cells by modulating secretion of interleukin 12 and interleukin 23 in response to stimulation with LPS.[37]

Ligands

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The D1 and D5 receptors have a high degree of structural homology and few ligands are available that can distinguish between them as yet. However, there is a number of ligands that are selective for D1/5 over the other dopamine receptors. The recent development of a selective D5 antagonist has allowed the action of D1-mediated responses to be studied in the absence of a D5 component, but no selective D5 agonists are yet available.

D5 receptors show higher affinity for agonists and lower affinity for antagonists than D1 receptors.[11]

Agonists

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Inverse agonists

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Antagonists

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  • 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol: antagonist, moderate binding selectivity over D1[40]
Chemical structure of a D5-preferring ligand 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol[40]

Protein–protein interactions

[edit]

D5 receptor has been shown to form heteromers with D2 receptors. Co-activation of these receptors within the heteromer triggers increase in intracellular calcium. This calcium signaling is dependent on Gq-11 protein signaling and phospholipase C, as well as on the influx of extracellular calcium.[41] Heteromers between D2 and D5 receptors are formed by adjacent arginines in ic3 (third cytoplasmic loop[42]) of D2 receptor and three adjacent c-terminus glutamic acids in D5 receptor. Heteromerization of 2 and D5 receptors can be disrupted through changes of single amino acids in the c-terminus of the D5 receptor.[12]

Dopamine receptor D5 has been shown to interact with GABRG2.[43]

Experimental methods

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The high degree of homology between D5 and D1 receptors and their affinity for drugs with similar pharmacological profile complicate distinguishing between them in research. Antibody staining these two receptors separately is suggested to be inefficient.[44] However, expression of D5 receptors has been assessed using immunohistochemistry. In this technique, two peptides were obtained from third extracellular loop and third intracellular loop of the receptor, and antisera were developed for staining the receptor in frozen mouse brain tissue.[35] A method involving mRNA probes for in situ hybridization has been developed, which allowed to separately examine the expression of D1 and D5 receptors in the mouse brain.[24]

DRD5 knockout mice can be obtained by crossing 129/SvJ1 and C57BL/6J mice.[10] D5 receptor can also be inactivated in an animal model by flanking the DRD5 gene with loxP site, allowing to generate tissue or animal lacking functional D5 receptors.[45] The expression of D5 receptor in vitro can also be silenced using antisense oligonucleotides.[20]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Dopamine receptor D5

View on Grokipedia
from Grokipedia
The dopamine receptor D5 (DRD5), also known as DRD5, is a subtype of that functions as a (GPCR) primarily activated by the , a key catecholamine involved in various neurological processes. It belongs to the D1-like family of , which also includes the D1 receptor, and is characterized by its coupling to stimulatory G proteins (Gαs/olf) that activate to increase intracellular cyclic AMP (cAMP) levels, thereby modulating downstream signaling via (PKA). Encoded by the DRD5 gene on , DRD5 features a classic seven-transmembrane domain structure typical of GPCRs, with a full-length protein sequence of 477 , though polymorphisms can result in a shorter 154-amino-acid variant. Compared to the D1 receptor, DRD5 exhibits higher sensitivity to (with lower EC50 values) and greater constitutive activity, but it desensitizes more rapidly upon prolonged agonist exposure. DRD5 is widely expressed in the central nervous system, with particularly high densities in the prefrontal cortex, striatum, nucleus accumbens, hippocampus, thalamus, and substantia nigra, where it often co-localizes with D1 or D2 receptors on neurons. Outside the brain, it is found in peripheral tissues including the kidney (where it regulates renin secretion and electrolyte balance), heart, adrenal glands, gastrointestinal tract, vasculature, and immune cells such as T-lymphocytes. This broad distribution underscores its multifaceted roles beyond neurotransmission, including contributions to renal vasodilation, immune modulation (e.g., T-cell adhesion and Th17 responses), and even retinal function in diabetic models. In the brain, DRD5 forms heterodimers with other receptors, such as GABA_A or NMDA receptors, which can fine-tune synaptic plasticity and signaling. Physiologically, DRD5 plays a critical role in cognitive processes like , , learning, and , as well as and reward pathways through its enhancement of thalamocortical transmission and modulation of . It also influences locomotion and may counteract opposing signals from D2-like receptors in balancing excitatory responses. In peripheral contexts, activation of DRD5 promotes and in the , helping maintain . Clinically, dysregulation of DRD5 has been implicated in several neuropsychiatric and neurological disorders, including , attention-deficit/hyperactivity disorder (ADHD)—where certain alleles are associated with increased risk (odds ratio ≈1.2)—, and , due to its involvement in dopamine-mediated and motor functions. Additionally, DRD5 contributes to mechanisms via descending dopaminergic pathways and L-DOPA-induced in Parkinson's treatment, positioning it as a potential therapeutic target for agonists or antagonists. Emerging research highlights its role in autoimmune conditions and antitumor immunity, suggesting broader pharmacological applications.

Molecular Structure and Genetics

Gene Location and Organization

The DRD5 gene, which encodes the dopamine receptor D5, is located on the short arm of human at position 4p16.1, with genomic coordinates spanning approximately 2,376 base pairs (GRCh38: 9,781,634–9,784,009). This locus is positioned centromeric to the gene (HTT) at 4p16.3, though it does not fall within the core Huntington's critical region. The gene structure consists of two exons separated by a small intron of variable size (134–156 base pairs) located entirely within the 5' untranslated region (UTR), rendering the protein-coding sequence intronless. Exon 1 encompasses non-coding sequence in the 5' UTR, while exon 2 contains the entire encoding the 477-amino-acid receptor protein, along with the 3' UTR. The DRD5 locus includes two related pseudogenes, DRD5P1 and DRD5P2, which feature sequences that result in premature truncation around residue 154. The transcriptional start site is situated approximately 2,125 base pairs upstream of the translation initiation codon. The promoter region features regulatory elements that modulate transcription, including a positive regulatory motif between positions -199 and -182 relative to the start site, which enhances expression, and a negative modulator spanning -500 to -251 that represses it. A notable polymorphic repeat (CT/GT/GA)_n in the 5' UTR exhibits 12 ranging from 134 to 156 bp in length, with the 148-bp showing biased transmission in attention-deficit/hyperactivity disorder (ADHD) cases, potentially influencing transcriptional efficiency. Among single nucleotide polymorphisms (SNPs), rs6283 (c.978C>T, p.Pro326=) is a common synonymous variant in the coding with a minor of approximately 0.35 in diverse populations, linked to variations in receptor expression levels and associations with traits such as and susceptibility. Evolutionarily, DRD5 demonstrates high sequence conservation across mammals, with the intronless coding architecture shared with the related DRD1 , reflecting an ancient duplication event predating divergence. This is preserved in most mammals, though independent inactivating mutations have occurred in cetaceans, leading to pseudogenization in some deep-diving species. Orthologs exist in 158 species, underscoring its fundamental role in signaling.

Protein Primary and Tertiary Structure

The human dopamine receptor D5 (DRD5), encoded by the DRD5 gene, is a 477-amino-acid polypeptide with a calculated molecular weight of approximately 52 kDa. As a class A G protein-coupled receptor (GPCR), its primary structure comprises an extracellular N-terminal domain, seven transmembrane helices (TM1 spanning residues 37–63, TM2 78–100, TM3 109–131, TM4 148–170, TM5 192–216, TM6 264–287, and TM7 311–334), three extracellular loops (ECL1 residues 64–77, ECL2 132–147, ECL3 288–310), three intracellular loops (ICL1 residues 101–108, ICL2 171–191, ICL3 217–263), and an intracellular C-terminal tail. Critical residues in the primary sequence include Asp103^{3.32} in TM3, which forms a with the group of for recognition, and the conserved DRY motif (Asp^{3.49}-Arg^{3.50}-Tyr^{3.51}, residues 124–126) at the end of TM3 extending into ICL2, which stabilizes the inactive state and facilitates G-protein coupling upon activation. The C-terminal tail, comprising residues 335–477, is approximately 31 longer than that of the closely related D1 receptor (DRD1, 446 total residues), enabling distinct interactions that influence signaling bias and receptor regulation. The tertiary structure of DRD5, determined by cryo-electron microscopy (cryo-EM) at 3.0 resolution in complex with Gs heterotrimer and the agonist (PDB: 8IRV), exhibits the canonical seven-transmembrane helical bundle characteristic of GPCRs, with the ligand-binding pocket located in the transmembrane core. The orthosteric binding site accommodates through interactions including a between Asp103^{3.32} and the ligand's , hydrogen bonds with Ser200^{5.42} and Asn292^{6.55}, and hydrophobic contacts with Trp82^{3.28}, Phe313^{7.35}, and Val317^{7.39}. Compared to DRD1, DRD5 displays nearly identical overall conformation (Cα RMSD of 0.48 ), but features a more negatively charged extracellular surface and stabilization of Trp157^{3.52} in the sodium-binding pocket, contributing to subtle differences in ligand potency. ECL2 and ICL3 exhibit flexibility and are partially unresolved, while the C-terminal tail remains disordered, consistent with its role in dynamic interactions. Post-translational modifications include potential N-linked at Asn5 and Asn11 in the N-terminal domain, which is essential for proper trafficking and plasma membrane expression of DRD5 but not DRD1. The C-terminal tail contains multiple serine and threonine residues (e.g., Ser408, Thr423) that serve as sites for GPCR kinases, modulating desensitization and internalization.

Signaling Pathways and Function

Activation Mechanism

The receptor D5 (D5R), a member of the D1-like subfamily of G protein-coupled receptors (GPCRs), is activated when binds to its orthosteric site within the transmembrane (TM) bundle. This binding occurs primarily through ionic interactions between the ligand's amine group and conserved aspartate residue Asp103^{3.32} in TM3, alongside hydrogen bonds with serine residues in TM5 and asparagine in TM6, stabilizing an active receptor conformation. This conformational shift involves the disruption of the ionic lock—a between Arg^{3.50} in TM3 and Glu^{6.30} in TM6—that maintains the inactive state in class A GPCRs, including D1-like receptors such as D5R; binding induces an outward movement of TM6, opening the intracellular G protein-binding pocket. Structural homology between D1R and D5R, sharing approximately 80% identity in their TM domains, supports this conserved activation dynamic for D5R. DRD5 also displays higher constitutive activity than D1R, contributing to basal Gs signaling. Upon activation, D5R preferentially couples to the stimulatory G proteins Gs or , facilitating GDP-to-GTP exchange on the Gα subunit and subsequent dissociation of the Gα-GTP complex from the Gβγ heterodimer. This uncoupling enables Gαs/olf to activate , though D5R also exhibits potential for coupling to other G proteins like Gq under certain conditions, reflecting functional versatility in signaling initiation. Allosteric modulation of D5R occurs at sites distinct from the orthosteric , including regions on extracellular loop 2 (ECL2) and intracellular loop 3 (ICL3), which can enhance or inhibit efficacy without competing for the primary . Positive allosteric modulators (PAMs), such as those selective for D1-like receptors, bind near the TM-III/V interface to stabilize active conformations and potentiate Gs coupling, offering improved selectivity over orthosteric s that often cross-react between D1R and D5R. A 2024 review highlights how such allosteric s can fine-tune D5R efficacy in CNS disorders by modulating these loop regions, reducing off-target effects compared to traditional agonists. D5R activation can exhibit biased agonism, where certain ligands preferentially recruit β-arrestin over G protein pathways, potentially leading to cAMP-independent signaling. For instance, some non-catechol agonists promote -biased responses at D5R while minimally recruiting β-arrestin, altering the balance of downstream effects without fully engaging arrestin-mediated pathways. Prolonged D5R activation triggers rapid desensitization through phosphorylation by G protein-coupled receptor kinase 2 (GRK2), which recruits β-arrestin to the receptor's C-terminal tail and ICL3, uncoupling it from G proteins and promoting clathrin-mediated internalization. This GRK2/β-arrestin mechanism, conserved across , limits sustained signaling and facilitates receptor recycling or degradation, though D5R-specific studies indicate relatively modest internalization kinetics compared to D2-like subtypes.

Downstream Effects

Upon activation, the dopamine receptor D5 (DRD5), a (GPCR), primarily couples to the stimulatory (Gs), leading to the activation of and a subsequent increase in intracellular (cAMP) levels. This elevation in cAMP then activates (PKA), which phosphorylates various downstream targets to mediate cellular responses. The cAMP-PKA pathway further promotes the phosphorylation of the cAMP response element-binding protein (CREB), a that binds to cAMP response elements (CRE) in the promoter regions of target genes, thereby influencing gene transcription. For instance, DRD5 activation has been shown to upregulate immediate early genes such as c-fos, which play roles in neuronal plasticity and adaptation. In addition to the canonical Gs-cAMP pathway, DRD5 signaling exhibits crosstalk with other intracellular cascades, including the (PI3K)/Akt pathway, which supports cell survival and anti-apoptotic effects, and the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, implicated in cellular proliferation and differentiation. These interactions allow for context-dependent modulation of signaling outputs. Tissue-specific downstream effects of DRD5 activation include, in neurons, the modulation of ion channels such as voltage-gated sodium and calcium channels, often enhancing neuronal excitability and promoting burst-firing in certain neuronal populations. In non-neuronal cells, such as vascular , DRD5 signaling promotes relaxation and through PKA-mediated inhibition of calcium influx. Feedback regulation of DRD5 occurs via PKA- and G protein-coupled receptor kinase (GRK)-mediated phosphorylation of the receptor, which facilitates β-arrestin recruitment, leading to desensitization, internalization, and potential tolerance to prolonged agonist exposure.

Expression Profile

In the Central Nervous System

The dopamine D5 receptor (D5R) exhibits high expression in several key regions of the central nervous system, including the prefrontal cortex, hippocampus, striatum, and substantia nigra. In the prefrontal cortex, D5R mRNA and protein are prominently detected in pyramidal neurons, contributing to cortical circuitry. Similarly, within the hippocampus, particularly the CA1 and dentate gyrus regions, D5R is localized to pyramidal and granule cells, supporting memory-related functions. In the striatum, expression is enriched in medium spiny neurons and interneurons, while in the substantia nigra pars compacta, it appears on dopaminergic neurons, influencing midbrain outputs. Notably, D5R colocalizes with D1 receptors in medium spiny neurons of the direct pathway in the . Recent studies have also identified D5R expression in within regions such as the and . At the synaptic level, D5R is predominantly postsynaptic, localized to dendritic spines in regions like the and hippocampus, where it modulates glutamatergic transmission. This positioning allows D5R to influence excitatory , such as , by altering trafficking and calcium dynamics in spines receiving asymmetric (excitatory) inputs. During development, D5R expression peaks in early to mid-adolescence across cortical and striatal regions, coinciding with heightened and circuit maturation that underpin behavioral transitions like increased risk-taking and learning flexibility. Post-adolescent levels decline gradually, reflecting stabilized adult circuitry. Species differences in D5R density and localization are evident, with primates (including humans) showing higher postsynaptic expression on dendritic spines and more extensive dendritic labeling in the striatum and hippocampus compared to rodents. In rodents, D5R is more presynaptic in certain areas like the amygdala, with overall lower cortical density, potentially contributing to divergent cognitive and reward processing capacities across species.

In Peripheral Organs

The dopamine receptor D5 (DRD5) is expressed in the , particularly in cells and renal vasculature, where it contributes to the regulation of by inhibiting sodium through downstream signaling that enhances and . In juxtaglomerular cells and associated vascular structures, DRD5 activation modulates renin release as part of the intrarenal system's interaction with the renin-angiotensin pathway, helping to control and . Human studies indicate that DRD5 mRNA expression is substantially elevated in the compared to , with levels reported up to 10-50 fold higher, underscoring its prominent peripheral role relative to distribution. In the heart, DRD5 is expressed in cardiac tissue, where it exerts cardioprotective effects by inhibiting (ROS) production, thereby mitigating and preventing progression to and failure; recent updates in genomic databases highlight this function in maintaining myocardial integrity. DRD5 is also present in other peripheral sites, including the , where it participates in endocrine regulation; vascular smooth muscle, facilitating via activation of calcium-dependent potassium channels that promote vessel relaxation; and immune cells such as T-lymphocytes, where it modulates activation, differentiation toward Th17 phenotypes, and overall immune responses.

Pharmacological Ligands

Agonists

The endogenous agonist for the dopamine D5 receptor is dopamine, which functions as a full agonist by activating Gs-coupled signaling pathways, including adenylyl cyclase stimulation and cyclic AMP accumulation. Dopamine exhibits approximately 10-fold higher binding affinity for the D5 receptor compared to the D1 receptor, with a pKi of 6.6 (Ki ≈ 251 nM) at D5, and functional potency reflected in an EC50 of around 1 μM in calcium signaling and cAMP assays. This differential affinity underscores the D5 receptor's role in fine-tuning dopaminergic responses in regions with overlapping D1/D5 expression. Among synthetic agonists, dihydrexidine stands out as a high-potency, full-efficacy selective for D1-like receptors, including D5, with binding affinities in the low nanomolar range (e.g., ≈ 10 nM at D1 and enhanced potency at D5 due to structural mimicry of dopamine's moiety). Its selectivity profile favors D1/D5 over D2-like receptors by over 100-fold, making it valuable for preclinical studies and PET imaging to assess receptor occupancy . Similarly, A-68930 is a potent, selective D1-like with an of 2.1 nM for activation, demonstrating full agonism at D5 while exhibiting minimal activity at D2-like subtypes ( > 3.9 μM), and has been instrumental in dissecting D5-mediated behaviors in animal models. Fenoldopam represents a non-selective D1-like agonist primarily targeting peripheral receptors, functioning as a with an of 57 nM for and , and showing comparable potency at both D1 and D5 without significant central penetration due to its hydrophilic nature. Recent advancements have drawn from natural products, particularly plant-derived alkaloids like tetrahydroprotoberberines, inspiring agonists such as (S)-(-)-stepholidine, which binds with Ki values of 5.1 nM at D1 versus 5.8 nM at D5, offering subtle selectivity and potential for subtype-specific therapeutic development. These compounds highlight evolving strategies to exploit D5's unique pharmacological profile for applications beyond traditional D1 targeting.

Antagonists and Inverse Agonists

The dopamine D5 receptor (D5R) is potently antagonized by selective D1-like blockers such as SCH-23390, a benzazepine with a Ki value of 0.3 nM at D5R, demonstrating high selectivity over D2-like subtypes. This compound competitively inhibits D5R activation without intrinsic activity, making it a prototypical neutral widely used in preclinical studies to dissect D1-like signaling. Similar benzazepines, including SCH-39166 (Ki ≈ 1.2 nM at D5R), exhibit comparable high-affinity blockade of D5R, reinforcing the pharmacological utility of this class for targeting D1-like receptors. Inverse agonists at D5R reduce the receptor's constitutive activity, which is notably higher in this subtype compared to other . Chlorpromazine functions as an at D1/D5 receptors, suppressing basal signaling in cellular models expressing wild-type D5R. Certain benzazepines also display inverse agonism at D5R, particularly in contexts of elevated basal tone, by stabilizing the inactive receptor conformation and diminishing agonist-independent cAMP production. This property distinguishes them from neutral antagonists and may contribute to therapeutic effects in disorders involving D5R hyperactivity. Non-selective antagonists like the atypical antipsychotic clozapine bind D5R with moderate affinity (weak antagonism reported across D1-like subtypes), alongside stronger interactions at D4 and serotonin receptors, contributing to its broad pharmacological profile. Haloperidol, a typical antipsychotic, primarily targets D2-like receptors but shows lower affinity for D5R, limiting its direct impact on D1-like pathways. Emerging allosteric antagonists for dopamine receptors, including those stabilizing inactive states of D1-like subtypes like D5R, have been reviewed in recent literature, offering potential for subtype-selective modulation without orthosteric competition. Pharmacokinetic considerations for D5R antagonists vary by application; CNS-targeted compounds such as SCH-23390 readily cross the blood-brain barrier, enabling central effects at low doses (e.g., 0.25 mg/kg in ). In contrast, peripheral-focused antagonists may exhibit restricted BBB penetration, supporting organ-specific interventions like in renal or without central side effects.

Clinical and Pathophysiological Roles

In Neurological Disorders

The dopamine D5 receptor plays a compensatory role in , where its expression is upregulated in the of animal models to counterbalance depletion in early stages. This upregulation occurs alongside broader changes in D1-like receptors, potentially aiding in maintaining motor function amid nigrostriatal degeneration. Selective D1/D5 agonists, such as tavapadon, have demonstrated enhanced motor benefits in preclinical PD models by stimulating striatal pathways without the dyskinesia risks associated with non-selective agents. As of September 2025, a for tavapadon has been submitted to the FDA. In studies of locomotion, dopamine D5 receptor knockout mice exhibit no significant deficits in baseline locomotor activity or exploratory behavior during open-field tests, indicating that D5 receptors are not essential for gross motor initiation. However, these mice display altered activity patterns in home-cage monitoring, with increased activity during certain diurnal phases and reduced behavioral flexibility in response to impulsive actions, suggesting a modulatory role in fine-tuned locomotor adjustments. No direct evidence links D5 receptor disruption to alterations in these models. The DRD5 gene, encoding the D5 receptor, maps to chromosome 4p16.1, proximal to the (HD) locus at 4p16.3, raising possibilities for its involvement as a genetic modifier. Genetic analyses have identified variants in the 4p16 region that influence HD age of onset. D5 receptors contribute to the modulation of hippocampal excitability, influencing neuronal firing and in regions vulnerable to epileptic activity. In seizure models, D5 receptor knockout mice display increased latency to onset and fewer electroencephalographic seizures following D1-like administration, indicating that D5 activation promotes hippocampal hyperexcitability and lowers . This suggests a pro-convulsant role for D5 in certain contexts, though broader modulation in remains receptor subtype-dependent. Recent investigations, including a 2024 review in the journal Receptors, emphasize the D5 receptor's distribution in nuclei such as the and , where it supports via direct pathway medium spiny neurons and . Dysregulation of D5 signaling in these circuits is implicated in motor impairments across neurodegenerative conditions, highlighting its therapeutic potential for targeted interventions.

In Psychiatric Disorders

The dopamine D5 receptor (D5R), a member of the D1-like family, plays a critical role in (PFC) function, where its hypofunction has been linked to cognitive deficits in . Dysregulation of D1-like receptor signaling, including D5R, in the dorsolateral PFC contributes to impairments in and executive function observed in patients with . Studies in animal models demonstrate that reduced D5R expression in the PFC leads to deficits in cognitive control and neuronal circuit oscillations necessary for and . In attention-deficit/hyperactivity disorder (ADHD), polymorphisms in the , such as the 148-bp repeat allele in a marker near the gene, are associated with increased risk and attention impairments. Meta-analyses confirm a small but significant association between DRD5 variants and ADHD susceptibility, particularly influencing inattentive subtypes and deficits. Preclinical studies using D5R mice reveal impairments in spatial tasks, while D1/D5 agonists, such as dihydrexidine, enhance performance in models of ADHD, suggesting potential therapeutic targeting to improve cognitive symptoms. D5R in the modulates reward processing and contributes to vulnerability, particularly through interactions with release induced by substances like . Activation of D5R facilitates reward signaling in this region, influencing motivational aspects of drug-seeking behavior. In smoking , enhances transmission that engages D5R, promoting and ; genetic variants in DRD5 have been implicated in severity, with preclinical evidence showing D5R blockade reduces nicotine-induced reward in animal models. D5R facilitates (LTP) in the hippocampus, a key mechanism for learning and . D1/D5 agonists enhance late-phase LTP in the CA1 region by promoting protein synthesis-dependent synaptic strengthening, which is essential for formation. In D5R mice, is selectively impaired in tasks like the Morris water maze, with deficits in hippocampal-dependent navigation and temporal order memory, underscoring D5R's role in cognitive processes relevant to psychiatric disorders.

In Cardiovascular and Renal Physiology

The (D5R) is expressed in renal proximal tubules, where its inhibits the Na⁺/H⁺ exchanger isoform 3 (NHE3), reducing sodium reabsorption and promoting and to maintain volume . This inhibitory effect on NHE3 occurs through D5R-coupled Gαs protein stimulation of , increasing cAMP levels and (PKA) activity, which phosphorylates and internalizes NHE3. Disruptions in D5R function, including single polymorphisms in the DRD5 at locus 4p15.1-16.1, impair this natriuretic response and are associated with by enhancing sodium retention. In regulation, D5R activation in vascular cells induces by elevating cAMP, which cross-activates to open large-conductance calcium- and voltage-activated potassium (BKCa) channels, leading to membrane hyperpolarization and relaxation. D5R deficiency, as observed in mice, results in salt-sensitive , with systolic elevated by approximately 27 mmHg (124 ± 2 mmHg versus 97 ± 3 mmHg in wild-type controls) due to impaired , increased , and heightened sympathetic tone. Emerging evidence highlights D5R's cardioprotective effects in cardiomyocytes, where activation reduces mitochondrial (ROS) production through cAMP-dependent , mitigating that contributes to ischemia-reperfusion injury. Overexpression of D5R in cardiomyocytes, conversely, exacerbates ROS generation and leads to , underscoring the receptor's normal role in maintaining balance. D5R expression on T cells modulates immune responses relevant to cardiovascular health, suppressing pro-inflammatory cytokine production such as interleukin-2 (IL-2) to limit inflammation that could exacerbate or vascular damage. This immunomodulatory function involves D5R signaling that reduces IL-2 secretion in CD4⁺ T cells, potentially attenuating systemic inflammatory contributions to salt-sensitive . In pathophysiological contexts, D5R polymorphisms increase susceptibility to by disrupting renal dopamine signaling and elevating via activation. Animal models of D5R knockout demonstrate elevations of 20-30 mmHg, primarily through renal mechanisms including upregulated sodium transporters (e.g., NHE3, Na⁺/K⁺-ATPase) and angiotensin II type 1 receptor expression, confirming D5R's essential role in preventing .

Protein-Protein Interactions

Identified Interactors

The dopamine receptor D5 (DRD5), a member of the D1-like subfamily of G protein-coupled receptors, engages in various protein-protein interactions that regulate its localization, signaling, and trafficking. These interactions have been identified through experimental methods such as co-immunoprecipitation, , and proximity ligation assays in cellular and animal models. Primary among these are couplings with heterotrimeric G proteins, which serve as direct transducers of receptor . DRD5 primarily couples to the stimulatory G proteins Gαs (GNAS) and Gαolf (GNAZ), activating to increase cyclic AMP levels. Evidence from biochemical assays in HEK293 cells and striatal neurons confirms that DRD5 activation leads to Gαs/olf dissociation and downstream effector engagement, with Gαolf predominating in olfactory and striatal regions. Additionally, DRD5 associates with Gα12 and Gα13 (GNA12/GNA13) in renal tissues, linking to non-canonical pathways like RhoA activation, as demonstrated by affinity purification and . For receptor regulation, β-arrestins, particularly β-arrestin-2 (ARRB2), bind to the third intracellular loop (ICL3) of DRD5 following agonist-induced , promoting desensitization, , and β-arrestin-biased signaling. This interaction was characterized in macrophages, where via DRD5-ARRB2 inhibits . DRD5 also forms heterodimers with other receptors, such as the D2 receptor (DRD2), generating intracellular via /11 pathways, as shown in heterologous systems and . Evidence for D1-D5 heteromers exists in the , where they regulate sodium transport. Scaffolding and regulatory proteins further modulate DRD5. Calcyon (CALY), an accessory protein, associates with DRD5 to promote clathrin-mediated endocytosis, demonstrated by enhanced internalization in calcyon-overexpressing cells. Enzymatic interactors include kinase 2 (GRK2), which phosphorylates DRD5 serine/ residues in the and ICL3, facilitating β-arrestin recruitment, confirmed by assays and in HEK cells. Database analyses provide a broader view of DRD5 interactome. The STRING database (version 12.5, as of 2025) identifies high-confidence partners (score >0.7), including , GNAZ, and , derived from curated and experimental data. BioGRID records 33 interactors for human DRD5, with physical interactions supported by low-throughput methods (e.g., GNAZ via affinity capture, GNA13 via co-purification), emphasizing and dominance.
Interactor CategorySpecific ProteinsInteraction TypeEvidence MethodKey Reference
G-proteinsGαs (GNAS), Gαolf (GNAZ), Gα12/13 (GNA12/GNA13)Physical (coupling)Co-IP, GTPγS bindingPMC5079267, AHA Journals
β-arrestinsβ-arrestin-2 (ARRB2)Physical (binding to ICL3)Co-IPMol Cell
Other receptorsD2 (DRD2)HeterodimerCo-IP, functional assaysBiol Psychiatry
EnzymesGRK2 (ADRBK1), calcyon (CALY)Phosphorylation/accessoryKinase assay, internalizationPMC5079267, PMC3442515

Biological Consequences

Interactions between the D5 receptor and β-arrestin 2 facilitate a shift from G protein-mediated cAMP pathways to β-arrestin-dependent activation of signaling cascades, such as in immune modulation where it blocks activation in macrophages. The D5-D2 receptor heteromer generates intracellular calcium signaling by different mechanisms, contributing to regulation of release in the and motivational behaviors. The calcyon-D5 receptor complex enhances calcium-dependent signaling and receptor trafficking in neurons, where calcyon acts as an adaptor to promote D5 internalization and recycling via endosomal pathways, thereby prolonging agonist-induced responses. In reward circuits, such as the and , this mechanism sustains D5-mediated excitation during prolonged release, supporting motivational behaviors and formation. In models, disruptions in D5 receptor protein interactions, including reduced heterodimerization and altered adaptor binding in the , impair oscillatory activity and circuits, leading to hyperdopaminergic states and cognitive deficits. For instance, knockdown of D5 receptors in rodent decreases gamma-band synchrony and elevates activity, mimicking schizophrenia-like impairments in executive function.

Recent Research Developments

Structural and Biophysical Studies

Recent advances in cryo-electron microscopy (cryo-EM) have elucidated the active-state structure of the D5 receptor (D5R) in complex with the Gs heterotrimer and the pan-agonist , achieving a resolution of 3.1 Å (PDB: 8IRV). This structure reveals the canonical GPCR activation mechanism, where agonist binding induces an outward displacement of transmembrane helix 6 (TM6) by approximately 7 Å relative to inactive conformations, enabling the intracellular core to accommodate the C-terminal α5 helix of Gαs and facilitating nucleotide exchange. The orthosteric binding pocket, located in the transmembrane domain's lower half, features key interactions between rotigotine's amine group and Asp^{3.32}, alongside hydrophobic contacts with residues like Ile^{3.33}, Phe^{6.51}, and Phe^{6.52}, which stabilize the in a pose conducive to receptor activation. Comparative structural analysis highlights similarities and subtle distinctions between D5R and the closely related D1 receptor (D1R), with the two sharing nearly identical backbone conformations (root-mean-square deviation of 0.48 Å over Cα atoms). However, D5R exhibits a wider orthosteric pocket due to minor adjustments in extracellular loop 2 (ECL2) positioning and residue orientations, such as the proximity of Phe^{7.35} to the ligand's moiety, allowing accommodation of bulkier agonists and contributing to D5R's higher potency for (pEC_{50} = 9.25) compared to D1R (pEC_{50} = 8.49). These differences underscore D5R's unique pharmacological profile within the D1-like subfamily, potentially influencing selectivity for therapeutic ligands. Additionally, molecules are observed binding between TM1-TM2 and TM3-TM4 interfaces, stabilizing the active conformation. Molecular dynamics (MD) simulations complement these static structures by demonstrating ligand-induced conformational flexibility, particularly in ECL2, which adopts a more dynamic orientation in D5R upon binding compared to D1R. This enhanced ECL2 mobility facilitates entry into the orthosteric site and modulates binding kinetics, with simulations revealing transient hydrogen bonding networks involving ECL2 residues that are less persistent in D1R models. Such insights address gaps in understanding subtype-specific activation barriers and support the design of D5R-selective modulators. Allosteric site mapping has identified intracellular positive allosteric modulators (PAMs) that bind distal to the orthosteric pocket, stabilizing the active TM6-out conformation without competing with endogenous . A 2024 review synthesizes evidence for D1-like receptor PAMs, including those targeting D5R, which enhance efficacy by promoting ICL2 α-helicity and coupling, offering a strategy to fine-tune signaling without altering orthosteric affinity. Biophysical assays further validate these dynamics: energy transfer (FRET) studies detect real-time conformational shifts in D5R upon engagement, particularly in D5R-D2R heteromers where activation reduces FRET efficiency by up to 20%, indicating spatial separation of receptor domains. () spectroscopy has probed binding kinetics, revealing slower off-rates for high-affinity D5R s compared to D1R, attributable to extended residence times in the flexible ECL2-flanked pocket. These techniques collectively bridge structural snapshots with functional dynamics, highlighting D5R's distinct activation landscape.

Therapeutic Targeting and Clinical Trials

The dopamine D5 receptor, as part of the D1-like family, has emerged as a promising target for novel therapies in neuropsychiatric and cardiovascular disorders, with recent efforts focusing on selective , allosteric modulators, and natural product-derived ligands to enhance therapeutic efficacy while minimizing side effects. D1/D5 agonists like dar-0100A have been investigated for cognitive deficits in , where preclinical and early clinical data suggest potential benefits through enhancement of prefrontal cortical function. A proof-of-concept of dar-0100A, a full at both D1 and D5 receptors, explored its role in cognitive enhancement but found that low doses achieving minimal receptor occupancy did not reliably improve cognition in patients with , highlighting the need for dose optimization in future studies. In , positive allosteric modulators (PAMs) of the D5 receptor offer a strategy to potentiate endogenous signaling without the dyskinetic risks of orthosteric agonists. Preclinical from 2024 indicate that D1-like PAMs, such as those targeting D5, enhance locomotor activity in reserpinized models and improve motor function in nonhuman primates, suggesting improved efficacy of levodopa therapy. Compounds like glovadalen, a selective D1 PAM with marginal activity at D5, are in phase 2 trials (as of 2025), with from the study presented in October 2025 demonstrating proof of mechanism, significant reduction in OFF time, and improved motor function in patients with motor fluctuations by modulating receptor sensitivity. Natural product-inspired scaffolds, particularly aporphines, have been explored for selective D5 agonism in addiction disorders. A 2024 study identified C10 nitrogen-containing aporphines with preferential binding to D1 over D5 receptors, but related tetrahydroprotoberberine derivatives like l-THP demonstrated efficacy in reducing drug self-administration and craving in preclinical models of , , and addiction; a 2008 pilot clinical study in 120 patients with addiction showed reduced craving and increased rates during post-acute withdrawal treatment. These ligands exhibit over 100-fold selectivity against serotonin 5-HT2A receptors, underscoring their potential for targeted D5 modulation in substance use disorders. Cardiovascular applications of D5 targeting include fenoldopam, a D1/D5 approved for severe , which lowers via and without significant . Derivatives and analogs continue to be investigated for refined selectivity, building on fenoldopam's established role in acute hypertensive emergencies. Preclinical evidence supports D5's cardioprotective effects in , where cardiac-specific D5 overexpression reduces and preserves function, while models exhibit and failure; ongoing research post-2024 explores translation to clinical trials for D5-mediated protection against remodeling. Therapeutic development faces challenges in selectivity, as many D5 ligands exhibit off-target binding to serotonin 5-HT receptors, potentially complicating neuropsychiatric applications. A 2024 review highlights that while natural product-derived agonists achieve high selectivity over 5-HT2A, broader polypharmacology remains a hurdle for D1/D5 compounds. Future directions emphasize biased agonists, which preferentially activate pathways over β-arrestin recruitment at D5, to mitigate in Parkinson's and enhance cognitive benefits in schizophrenia without adverse effects.

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