Dopamine receptor D5

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

Function
D5 receptor is a subtype of the dopamine receptor that has a 10-fold higher affinity for dopamine than the D1 subtype. The D5 subtype is a is_associated_with::G-protein coupled receptor, which promotes synthesis of cAMP by is_associated_with::adenylyl cyclase via activation of Gαs/olf family of G proteins. Both D5 and D1 subtypes activate is_associated_with::adenylyl cyclase. D1 receptors were shown to stimulate monophasic dose-dependent accumulation of cAMP in response to is_associated_with::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.

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

is_associated_with::In vitro, D5 receptors show high constitutive activity that is independent of binding any is_associated_with::agonists.

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 is_associated_with::C-terminus of 93 is_associated_with::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. The entire amino acid sequence of D5 receptor in is_associated_with::homo sapiens can be found here.

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 is_associated_with::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 is_associated_with::stop codons that prevent these genes from transcribing a functional protein.

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

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

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

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 is_associated_with::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 is_associated_with::amygdala. It has been shown that M1-Muscarinic receptors cooperate with D5 receptors and is_associated_with::beta-2 adrenergic receptors to consolidate cued fear memory. It is suggested that these is_associated_with::G protein-coupled receptors redundantly activate is_associated_with::phospholipase C in is_associated_with::basolateral amygdala. One effect of the activation of phospholipase C is deactivation of KCNQ channels. Since KCNQ channels conduct is_associated_with::M current that raises the threshold for is_associated_with::action potential, deactivation of these channels leads to increased neuronal excitability and enhanced memory consolidation.

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

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 146-bp allele of DRD5 was shown to be a is_associated_with::risk factor for it. There exist two types of the 146-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 is_associated_with::pyramidal cell somas. Deficiency in D5 receptors may contribute to learning problems that may be associated with ADHD.

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

Parkinson's disease
D5 receptors may be involved in burst firing of is_associated_with::subthalamic nucleus neurons in 6-OHDA rat model of is_associated_with::Parkinson's disease. In this animal model, blockage of D5 receptors with is_associated_with::flupentixol reduces burst firing and improves motor deficits. One study shows that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations in PD.

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

Locomotion
D5 receptor is believed to participate in modulation of psychostimulant-induced is_associated_with::locomotion. Mice lacking D5 receptors show increased motor response to administration of is_associated_with::methamphetamine than is_associated_with::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 is_associated_with::blood pressure. Mice lacking this receptor in their brains showed is_associated_with::hypertension and elevated is_associated_with::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 is_associated_with::renalase and excretion of is_associated_with::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 is_associated_with::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 is_associated_with::mRNA of IFNγ, the expression of IFNγ protein is diminished.

D5 receptors are involved in activation and differentiation of is_associated_with::T helper 17 cells. Specifically, these receptors play a role in polarization of CD4+ T-cells into the is_associated_with::T helper 17 cells by modulating secretion of is_associated_with::interleukin 12 and is_associated_with::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 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 that D1 receptors.

Agonists

 * is_associated_with::Dihydrexidine
 * is_associated_with::Rotigotine
 * is_associated_with::SKF-83,959
 * is_associated_with::Stepholidine
 * is_associated_with::Fenoldopam

Inverse agonists

 * is_associated_with::Flupentixol

Antagonist s

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


 * is_associated_with::SCH 23390

Protein-protein interactions
D5 receptor has been shown to form is_associated_with::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 is_associated_with::Phospholipase C, as well as on the influx of extracellular is_associated_with::calcium. Heteromers between D2 and D5 receptors are formed by adjacent is_associated_with::arginines in ic3 (third cytoplasmic loop ) of D2 receptor and three adjacent is_associated_with::c-terminus is_associated_with::glutamic acids in D5 receptor. Heteromerization of 2 and D5 receptors can be disrupted through changes of single amino acids in the is_associated_with::c-terminus of the D5 receptor.

Dopamine receptor D5 has been shown to interact with is_associated_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 is_associated_with::immunohistochemistry. In this technique, two is_associated_with::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. A method involving mRNA probes for is_associated_with::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 is_associated_with::C57BL/6J mice. D5 receptor can also be inactivated in an is_associated_with::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.