scholarly journals Differential receptor crosstalk in DRD1-DRD2 heterodimer upon phasic and tonic dopamine signals

2021 ◽  
Author(s):  
Hyunbin Kim ◽  
Min-Ho Nam ◽  
Sohyeon Jeong ◽  
Hyowon Lee ◽  
Soo-Jin Oh ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Camp Level ◽  
Receptor Subtypes ◽  
Dopamine Level ◽  
Individual Activity ◽  
Time Activity ◽  
Downstream Signaling ◽  
Receptor Crosstalk

In response to phasic and tonic release, dopamine neurotransmission is regulated by its receptor subtypes, mainly dopamine receptor type 1 and 2 (DRD1 and DRD2). These dopamine receptors are known to form a heterodimer, however the receptor crosstalk between DRD1 and DRD2 was only suspected by measuring their downstream signaling products, due to the lack of methodology for selectively detecting individual activity of different dopamine receptors. Here, we develop red DRD1 sensor (R-DRD1) and green DRD2 sensor (G-DRD2) which can specifically monitor the real-time activity of DRD1 and DRD2, and apply these multicolor sensors to directly measure the receptor crosstalk in the DRD1-DRD2 heterodimer. Surprisingly, we discover that DRD1 activation in the heterodimer is inhibited only at micromolar phasic concentration of dopamine, while DRD2 activation is selectively inhibited at nanomolar tonic dopamine level. Differential receptor crosstalk in the DRD1-DRD2 heterodimer further modulates their downstream cAMP level. These data imply a novel function of the DRD1-DRD2 heterodimer at physiological dopamine levels of phasic and tonic release. Our approach utilizing multicolor receptor sensors will be useful to discover novel function of GPCR heterodimers.

scholarly journals Quantification of [11C]FLB 457 Binding to Extrastriatal Dopamine Receptors in the Human Brain

1999 ◽  
Vol 19 (10) ◽  
pp. 1164-1173 ◽  
Author(s):  
Hans Olsson ◽  
Christer Halldin ◽  
Carl-Gunnar Swahn ◽  
Lars Farde
Keyword(s):  
Human Brain ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Compartment Model ◽  
Binding Potential ◽  
Receptor Subtypes ◽  
D2 Dopamine Receptor ◽  
Reliable Determination ◽  
Three Compartment Model ◽  
Dopamine Receptor Binding

Positron emission tomography (PET) has hitherto been used to examine D2 dopamine receptor binding in the striatum, a region with a high density of receptors. Research has been hampered by the lack of suitable radioligands for detection of the low-density D2 dopamine receptor populations in the limbic and cortical dopamine systems that are implicated in the patophysiology of schizophrenia. [11C]FLB 457 is a new radioligand with the very high affinity of 20 pmol/L (Ki) for the D2 and D3 dopamine receptor subtypes. This study in eight healthy subjects was designed to evaluate the suitability of [11C]FLB 457 for quantification of extrastriatal D2/D3 dopamine receptors. PET-data were acquired in the three-dimensional mode and the arterial input function was corrected for labeled metabolites. The standard three-compartment model and four derived approaches were applied to calculate and compare the binding potentials. Besides the striatum, conspicuous radioactivity was found in extrastriatal regions such as the thalamus, the anterior cinguli, and the temporal and frontal cortices. The time activity curves could be described by the three compartment model. The different approaches gave similar binding potential values and the rank order between regions was consistent with that found in vitro. The short time of a PET measurement using [11C]FLB 457 (63 minutes) seemed not to be sufficient for reliable determination of the high binding potential in the striatum. These results are of principal importance because they show the potential for PET quantification of minute receptor populations in the human brain.

scholarly journals Molecular modelling of D2-like dopamine receptors

1992 ◽  
Vol 287 (1) ◽  
pp. 277-282 ◽  
Author(s):  
C D Livingstone ◽  
P G Strange ◽  
L H Naylor
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Three Dimensional ◽  
Transmembrane Domains ◽  
Receptor Subtypes ◽  
Alpha Helices ◽  
Dopamine Receptor Subtypes ◽  
Membrane Bound ◽  
Agonist Ligands ◽  
Sequence Similarities

Three-dimensional computer models of the rat D2, D3 and D4 dopamine receptor subtypes have been constructed based on the diffraction co-ordinates for bacteriorhodopsin, another membrane-bound protein containing seven transmembrane domains presumed to be arranged in a similar spatial orientation. Models were assembled by aligning the putative transmembrane domains of the dopamine receptors with those of bacteriorhodopsin using sequence similarities, and then superimposing these modelled alpha-helices on to the bacteriorhodopsin-derived co-ordinates. These models explore the potential hydrogen bonding, electrostatic and stacking interactions within the receptor which may be important for maintaining the conformation of these receptors, and thereby provide target sites for agonist binding. Proposed interactions between the catecholamine ligands and these receptors appear to account for the affinity, although not the specificity, of these agonist ligands for the different dopamine receptor subtypes. Such models will be useful for establishing structure-function relationships between ligands and the dopamine receptors, and may ultimately provide a template for the design of receptor-specific drugs.

scholarly journals The renal dopamine receptors.

1992 ◽  
Vol 2 (8) ◽  
pp. 1265-1278
Author(s):  
P A Jose ◽  
J R Raymond ◽  
M D Bates ◽  
A Aperia ◽  
R A Felder ◽  
...  
Keyword(s):  
Amino Acids ◽  
Adenylyl Cyclase ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
D2 Receptor ◽  
D2 Receptors ◽  
Receptor Subtypes ◽  
Renal Dopamine ◽  
The Brain ◽  
Stimulation Of

Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.

Renal Dopamine Receptors and Hypertension

2003 ◽  
Vol 228 (2) ◽  
pp. 134-142 ◽  
Author(s):  
Tahir Hussain ◽  
Mustafa F. Lokhandwala
Keyword(s):  
Proximal Tubule ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Sodium Excretion ◽  
Molecular Mechanisms ◽  
Sympathetic Ganglia ◽  
Receptor Subtypes ◽  
Receptor Function ◽  
The Central Nervous System ◽  
Renal Dopamine

Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which Include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D1 receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D1 receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

Dopamine Receptors and Antipsychotic Drug Response

1993 ◽  
Vol 163 (S22) ◽  
pp. 31-38 ◽  
Author(s):  
Roger K. Sunahara ◽  
Philip Seeman ◽  
Hubert H. M. Van Tol ◽  
Hyman B. Niznik
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Antipsychotic Drug ◽  
Drug Response ◽  
Chromosomal Location ◽  
Receptor Subtypes ◽  
Receptor System ◽  
Dopamine Receptor Genes ◽  
The Brain ◽  
Receptor Family

Dopamine receptors have been divided into two major types – D1 and D2 – based primarily on pharmacological and biochemical criteria. Recent advances in the molecular biology of the dopamine receptor system have allowed the identification and characterisation of at least five distinct neuronal dopamine receptor genes (D1 to D5). These genes encode dopamine receptors belonging to the D1 receptor family, termed D1 and D5, and three D2-like receptors, termed D2, D3 and D4. These receptors are distinguished on the basis of their primary structure, chromosomal location, mRNA size and tissue distribution, and biochemical and pharmacological differences. Although individually these receptor subtypes may not be directly and exclusively involved in the maintenance or expression of schizophrenia, alterations of any of the receptors may contribute to the perturbation or instability of dopaminergic homeostasis in the brain. What was once thought to be a simple two-receptor system seems to have emerged as an intricate and interactive entity. This review summarises what is currently understood about dopamine receptors, their role in antipsychotic drug action, and their association with psychosis.

scholarly journals Classification of Dopamine Receptor Genes in Vertebrates: Nine Subtypes in Osteichthyes

2015 ◽  
Vol 86 (3-4) ◽  
pp. 164-175 ◽  
Author(s):  
Kei Yamamoto ◽  
Romain Fontaine ◽  
Catherine Pasqualini ◽  
Philippe Vernier
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Animal Studies ◽  
Phylogenetic Analyses ◽  
D2 Receptor ◽  
Receptor Subtypes ◽  
Brain Functions ◽  
History Of ◽  
Dopamine Receptor Genes ◽  
G Protein Coupled

Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates.

The dopamine receptor in adult and maturing kidney

1989 ◽  
Vol 257 (3) ◽  
pp. F315-F327 ◽  
Author(s):  
R. A. Felder ◽  
C. C. Felder ◽  
G. M. Eisner ◽  
P. A. Jose
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adenylate Cyclase ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
The Central Nervous System ◽  
Renal Tubular ◽  
Da2 Receptor

Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.

The dopaminergic system in hypertension

2007 ◽  
Vol 112 (12) ◽  
pp. 583-597 ◽  
Author(s):  
Chunyu Zeng ◽  
Meng Zhang ◽  
Laureano D. Asico ◽  
Gilbert M. Eisner ◽  
Pedro A. Jose
Keyword(s):  
Blood Pressure ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Epithelial Transport ◽  
Receptor Subtypes ◽  
Smooth Muscle Contractility ◽  
Dopamine Receptor Subtypes ◽  
Sympathetic Nervous Systems ◽  
The Relationship ◽  
Regulation Of Blood Pressure

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin–angiotensin and sympathetic nervous systems. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3 and D4) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. This review summarizes the physiology of the different dopamine receptors in the regulation of blood pressure, and the relationship between dopamine receptor subtypes and hypertension.

scholarly journals The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 139
Author(s):  
Waleed N. Qaddumi ◽  
Pedro A. Jose
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Dopaminergic System ◽  
Receptor Subtypes ◽  
The Many ◽  
Renal Dopamine ◽  
Regulation Of Blood Pressure ◽  
And Oxidative Stress

The kidney is critical in the long-term regulation of blood pressure. Oxidative stress is one of the many factors that is accountable for the development of hypertension. The five dopamine receptor subtypes (D1R–D5R) have important roles in the regulation of blood pressure through several mechanisms, such as inhibition of oxidative stress. Dopamine receptors, including those expressed in the kidney, reduce oxidative stress by inhibiting the expression or action of receptors that increase oxidative stress. In addition, dopamine receptors stimulate the expression or action of receptors that decrease oxidative stress. This article examines the importance and relationship between the renal dopaminergic system and oxidative stress in the regulation of renal sodium handling and blood pressure. It discusses the current information on renal dopamine receptor-mediated antioxidative network, which includes the production of reactive oxygen species and abnormalities of renal dopamine receptors. Recognizing the mechanisms by which renal dopamine receptors regulate oxidative stress and their degree of influence on the pathogenesis of hypertension would further advance the understanding of the pathophysiology of hypertension.

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