Dopamine receptor D5

Primary structure

D₅ receptor is highly homologous to the D₁ receptor. Their amino acid sequences are 49% to 80% 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.

Chromosomal location

In humans, D₅ receptor is encoded on the chromosome 4p15.1–p15.3. The gene lacks introns and encodes a product of 477 amino acids. 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.

Expression

Central nervous system

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

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

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. D₅ receptors are thought to positively regulate expression of renalase. Their faulty functioning in nephrons can contribute to hypertension.

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. 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. Since KCNQ channels conduct M current that raises the threshold for action potential, deactivation of these channels leads to increased neuronal excitability and enhanced memory consolidation.

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

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.

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. 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. Another allele of DRD5 that is moderately associated with ADHD susceptibility is 150 bp. 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.

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. 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.

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. Some single-nucleotide polymorphisms in this gene, including changes in rs77434921, rs1800762, rs77434921, and rs1800762, in northern Han Chinese population.

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, 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. 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.

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.

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.

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 D_1/5 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.

Agonists

• Dihydrexidine
• Rotigotine
• SKF-83,959
• Stepholidine
• Fenoldopam

Inverse agonists

• Flupentixol

Antagonists

• 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol: antagonist, moderate binding selectivity over D₁

• SCH 23390

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. Heteromers between D₂ and D₅ receptors are formed by adjacent arginines in ic3 (third cytoplasmic loop) 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.

Dopamine receptor D₅ has been shown to interact with GABRG2.

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. 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. 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.

DRD5 knockout mice can be obtained by crossing 129/SvJ1 and C57BL/6J mice. 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. The expression of D₅ receptor in vitro can also be silenced using antisense oligonucleotides.