-
Life Sciences Nov 2022Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall... (Review)
Review
Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall behavior. Thus, dopamine receptor antagonist antipsychotic drugs are commonly used to treat multiple psychiatric disorders. Although less discussed, these receptors are also expressed in other peripheral organ systems, such as the kidneys, eyes, gastrointestinal tract, and cardiac tissue. Consequently, therapies for certain psychiatric disorders which target dopamine receptors could have unidentified consequences on certain functions of these peripheral tissues. The existence of an intrinsic dopaminergic system in the human heart remains controversial and debated within the literature. Therefore, this review focuses on literature related to dopamine receptors within cardiac tissue, specifically dopamine receptor 3 (D3R), and summarizes the current state of knowledge while highlighting areas of research which may be lacking. Additionally, recent findings regarding crosstalk between D3R and dopamine receptor 1 (D1R) are examined. This review discusses the novel concept of understanding the role of the loss of function of D3R may play in collagen accumulation and cardiac fibrosis, eventually leading to heart failure.
Topics: Animals; Antipsychotic Agents; Dopamine; Dopamine Agonists; Dopamine Antagonists; Fibrosis; Humans; Mammals; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 36041503
DOI: 10.1016/j.lfs.2022.120918 -
Pharmacological Reviews Mar 2011G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from... (Review)
Review
G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Gene Expression Regulation; Humans; Ligands; Molecular Targeted Therapy; Receptors, Dopamine; Signal Transduction
PubMed: 21303898
DOI: 10.1124/pr.110.002642 -
Current Opinion in Neurology and... Aug 1993Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search... (Review)
Review
Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search for and discovery of more selective antipsychotic and antiparkinson drugs. The D1-like dopamine receptors, D1 and D5, are sensitive to the same drugs as the D1 receptor in native tissues, but D5 is about 10 times more sensitive to dopamine than D1. The D2-like receptors, D2, D3, and D4, have approximately similar sensitivities to dopamine, but bromocriptine and raclopride are both about two orders of magnitude weaker at D4, whereas clozapine is one order more potent at D4, as compared with D2 and D3. The human dopamine D4 receptor has many variants. The sensitivities to clozapine of human variants D4.2, D4.4, and D4.7 are approximately similar, with dissociation constants between 5 and 24 nM, matching the spinal fluid concentration of clozapine under therapeutic conditions. Thus antipsychotic action may be effected through blockade of either dopamine D2 or D4 receptors.
Topics: Animals; Antiparkinson Agents; Antipsychotic Agents; Brain; Clozapine; Humans; Parkinson Disease; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia
PubMed: 8104554
DOI: No ID Found -
Physiological Reviews Jan 1998The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5)... (Review)
Review
The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2, D3, and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.
Topics: Animals; Animals, Genetically Modified; Brain; Gene Expression Regulation; Humans; Hypertension; Mice; Pituitary Gland; Receptors, Dopamine; Signal Transduction
PubMed: 9457173
DOI: 10.1152/physrev.1998.78.1.189 -
Progress in Brain Research 2014Dopamine neurotransmission is traditionally accepted as occurring through the five dopamine receptors that transduce its signal. Recent evidence has demonstrated that... (Review)
Review
Dopamine neurotransmission is traditionally accepted as occurring through the five dopamine receptors that transduce its signal. Recent evidence has demonstrated that the range of physiologically relevant dopamine signaling complexes is greatly expanded by the ability of dopamine receptors to interact with other dopamine receptors and with receptors of other endogenous signaling ligands. These novel heteromeric complexes have functional properties distinct from the component receptors or are able to modulate the canonical signaling and function of the cognate receptors. These dopamine receptor heteromers provide new insight into physiological mechanisms and pathophysiological processes involving dopamine.
Topics: Animals; Brain; Dopamine; Humans; Receptors, Dopamine; Signal Transduction; Synaptic Transmission
PubMed: 24968781
DOI: 10.1016/B978-0-444-63425-2.00008-8 -
Neuroscience and Biobehavioral Reviews 1995Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to... (Review)
Review
Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to ontogenetic aspects of this process was reviewed. Neonatal 6-hydroxydopamine (6-OHDA) destruction of rat brain DA neurons produces overt sensitization to D1 agonist-induced oral activity, overt sensitization of some D2 agonist-induced stereotyped behaviors and latent sensitization of D1 agonist-induced locomotor and some stereotyped behaviors. This last process is unmasked by repeated treatments with D1 (homologous "priming") or D2 (heterologous "priming") agonists. A serotonin (5-HT) neurotoxin (5,7-dihydroxytryptamine) and 5-HT2C receptor antagonist (mianserin) attenuate some enhanced behavioral effects of D1 agonists, indicating that 5-HT neurochemical systems influence D1 receptor sensitization. Unlike the relative absence of change in brain D1 receptor number, DA D2 receptor proliferation accompanies D2 sensitization in neonatal 6-OHDA-lesioned rats. Robust D2 receptor supersensitization can also be induced in intact rats by repeated treatments in ontogeny with the D2 agonist quinpirole. In these rats quinpirole treatments produce vertical jumping at 3-5 wk after birth and subsequent enhanced quinpirole-induced antinociception and yawning. The latter is thought to represent D3 receptor sensitization. Except for enhanced D1 agonist-induced expression of c-fos, there are no changes in the receptor or receptor-mediated processes which account for receptor sensitization. Adaptive mechanisms by multiple "in series" neurons with different neurotransmitters may account for the phenomenon known as receptor supersensitivity.
Topics: Animals; Dopamine Agonists; Rats; Receptors, Dopamine
PubMed: 7770190
DOI: 10.1016/0149-7634(94)00019-w -
Journal of Psychiatry & Neuroscience :... Oct 1992For over a decade it has been generally assumed that all the pharmacological and biochemical actions of dopamine within the central nervous system and periphery were... (Review)
Review
For over a decade it has been generally assumed that all the pharmacological and biochemical actions of dopamine within the central nervous system and periphery were mediated by two distinct dopamine receptors. These receptors, termed D1 and D2, were defined as those coupled to the stimulation or inhibition of adenylate cyclase, respectively, and by their selectivity and avidity for various drugs and compounds. The concept that two dopamine receptors were sufficient to account for all the effects mediated by dopamine was an oversimplification. Recent molecular biological studies have identified five distinct genes which encode at least eight functional dopamine receptors. The members of the expanded dopamine receptor family, however, can still be codifed by way of the original D1 and D2 receptor dichotomy. These include two genes encoding dopamine D1-like receptors (D1 [D1A]/D5 [D1B]) and three genes encoding D2-like receptors (D2/D3/D4). We review here our recent work on the cloning and characterization of some of the members of the dopamine receptor gene family (D1, D2, D4, D5), their relationship to neuropsychiatric disorders and their potential role in antipsychotic drug action.
Topics: Amino Acid Sequence; Animals; Brain; Cloning, Molecular; Clozapine; Dopamine; Humans; Molecular Sequence Data; RNA, Messenger; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology
PubMed: 1450188
DOI: No ID Found -
Brain, Behavior and Evolution 2015Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2... (Review)
Review
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.
Topics: Animals; Biological Evolution; Fish Proteins; Fishes; Receptors, Dopamine; Terminology as Topic
PubMed: 26613258
DOI: 10.1159/000441550 -
Trends in Pharmacological Sciences Jun 1990The D1/D2 dopamine receptor classification is widely accepted. However, intense investigative efforts over the last several years using pharmacological, biochemical and... (Review)
Review
The D1/D2 dopamine receptor classification is widely accepted. However, intense investigative efforts over the last several years using pharmacological, biochemical and behavioral approaches have produced results that are increasingly difficult to reconcile with the existence of only two dopamine receptor subtypes. Recent developments, including cloning of the cDNAs and/or genes for several members of the large family of G-protein-coupled receptors, have revealed that heterogeneity in the pharmacological or biochemical characteristics of individual receptors often indicates the presence of previously unsuspected molecular subtypes. In this article, Marc Caron and colleagues have assembled the main lines of evidence that suggest the presence of several novel subtypes for both D1 and D2 dopamine receptors and predict that molecular cloning will, in the near future, confirm their existence.
Topics: Animals; Humans; Receptors, Dopamine; Terminology as Topic
PubMed: 2200181
DOI: 10.1016/0165-6147(90)90249-8 -
CNS & Neurological Disorders Drug... Feb 2006The classification of dopamine receptors proposed more than two decades ago remains valid today. Based on biochemical and pharmaceutical properties two main classes of... (Review)
Review
The classification of dopamine receptors proposed more than two decades ago remains valid today. Based on biochemical and pharmaceutical properties two main classes of dopamine receptors can be distinguished: D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), and D(4)) dopamine receptors. Dopamine receptors belong to the class of G protein-coupled receptors and signal to a wide range of membrane bound and intracellular effectors such as ion channels, secondary messenger systems and enzymes. Although the pharmacological properties of ligands for D(1)-like and D(2)-like dopamine receptors are quite different, the number of selective ligands for each of the five receptors subtypes is rather small. Many drugs used to treat neurological and neuropsychiatric disorders like Parkinson's disease, restless leg syndrome and schizophrenia have affinities for dopamine receptors. Such medications are not without limitations so the development of novel (selective or aselective) dopamine receptor ligands is of the utmost importance for improved therapeutic approaches for these diseases. In that respect it is also important to understand how dopamine receptor ligands affect receptor signalling processes such as desensitization, receptor heterodimerization and agonist-receptor trafficking, issues which will be discussed in the present review. Furthermore, attention is paid to interactions of dopamine receptors with serotonin receptors since many drugs used to treat above mentioned disorders of the brain also possess affinities for serotonin receptors. Because of the enormity of this area we have tried to focus more specifically on interactions within the prefrontal cortex where it appears that the serotonergic modulation of dopaminergic function might be very relevant to schizophrenia.
Topics: Animals; Antipsychotic Agents; Brain; Dimerization; Dopamine Agents; Humans; Ligands; Receptor Cross-Talk; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Signal Transduction
PubMed: 16613551
DOI: 10.2174/187152706784111614