Dopamine receptor D5

Last updated

DRD5
Identifiers
Aliases DRD5 , DBDR, DRD1B, DRD1L2, dopamine receptor D5
External IDs OMIM: 126453 MGI: 94927 HomoloGene: 20216 GeneCards: DRD5
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 Mb Chr 5: 38.48 – 38.48 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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.

Contents

Function

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

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

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

Central nervous system

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

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

Learning and memory

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

Smoking

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

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

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

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

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

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

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

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

Inverse agonists

Antagonists

Chemical structure of a D5-preferring ligand 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz-d,g-azecin-3-ol.png
Chemical structure of a D5-preferring ligand 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol

Protein–protein interactions

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

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 exracellular 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

Related Research Articles

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

Dopamine receptor D<sub>4</sub> Protein-coding gene in the species Homo sapiens

The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist(DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. The use of dopamine agonists is associated with impulse control disorders and dopamine agonist withdrawal syndrome (DAWS).

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.

A heteromer is something that consists of different parts; the antonym of homomeric. Examples are:

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

Dopamine receptor D<sub>1</sub> Protein-coding gene in humans

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5-HT<sub>2C</sub> receptor Serotonin receptor protein distributed mainly in the choroid plexus

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5-HT<sub>1B</sub> receptor Mammalian protein found in Homo sapiens

5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.

Muscarinic acetylcholine receptor M<sub>4</sub> Protein-coding gene

The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.

<span class="mw-page-title-main">TAAR2</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene. TAAR2 is coexpressed with Gα proteins; however, as of February 2017, its signal transduction mechanisms have not been determined.

Dopamine receptor D<sub>3</sub> Subtype of Dopamine Receptor

Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.

Prostaglandin EP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GNAI3</span> Protein-coding gene in humans

Guanine nucleotide-binding protein G(k) subunit alpha is a protein that in humans is encoded by the GNAI3 gene.

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<span class="mw-page-title-main">Olivier Civelli</span> Molecular biologist

Olivier Civelli is a molecular biologist, a researcher in the field of neuropharmacology and an educator. He is the Eric L. and Lila D. Nelson Professor of Neuropharmacology at University of California, Irvine. He is also a Professor in the Department of Developmental and Cell Biology at University of California, Irvine. He is most known for his work in advancing understanding of neurotransmission and his impact on drug discovery.

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