Molecular Characteristics of Mammalian Dopamine Receptors

Lachowicz, Jean E.; Sibley, David R.

doi:10.1111/j.1600-0773.1997.tb00039.x

Cited by 115 publications

(84 citation statements)

References 78 publications

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“…Analysis of the amino acid sequences of the dopamine receptor subtypes reveals that there is a high degree of homology between the members of the subfamilies (43). The genomic organization of the dopamine receptors also supports the notion that they derive from the divergence of two gene subfamilies (49).…”

Section: Introductionmentioning

confidence: 50%

SCH 23390: The First Selective Dopamine D₁‐Like Receptor Antagonist

2001

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SCH 23390, the halobenzazepine (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, is a highly potent and selective dopamine D 1 -like receptor antagonist with a K i of 0.2 and 0.3 nM for the D 1 and D 5 dopamine receptor subtypes, respectively. In vitro, it also binds with high affinity to the 5-HT 2 and 5-HT 1C serotonin receptor subtypes. However, the doses required to induce a similar response in vivo are greater than 10-fold higher than those required to induce a D 1 -mediated response.Previous in vivo pharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D 1 -like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D 1 receptors facilitates seizure activity, whereas activation of D 2 receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D 1 receptors in rodents, nonhuman primates, and humans.In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D 1 receptor, in neurological function and dysfunction.

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Section: Introductionmentioning

confidence: 50%

SCH 23390: The First Selective Dopamine D₁‐Like Receptor Antagonist

2001

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“…Dopamine is a catecholarnine that acts as a neurotransmitter in the brain and in the paiphery, Dopamine acts as a modulator of caràiovascular îünction, hormone secretion, vascular tone, rend function and gastrointestinal motility (for comprehensive and recent reviews see Lachowicz and Sibley, 1997;Missale et al, 1998;Wilson et al, 1998). In the central nervous systern (CNS) the doparninergic systern has been shown to be involved in motor and endocrine control, emotion, reward and cognition.…”

Section: The Dopamine Systemmentioning

confidence: 99%

SH3 Binding Domains in the Dopamine D4 Receptor

Oldenhof

Vickery²,

Anafi³

et al. 1998

Biochemistry

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The dopamine D4 receptor is a G protein-coupled receptor (GPCR) that belongs to the dopamine D2-like receptor family. Functionally, the D2-like receptors are characterized by their ability to inhibit adenylyl cyclase. The dopamine D4 receptor as well as many other catecholaminergic receptors contain several putative SH3 binding domains. Most of these sites in the D4 receptor are located in a polymorphic repeat sequence and flanking sequences in the third intracellular loop. Here we demonstrate that this region of the D4 receptor can interact with a large variety of SH3 domains of different origin. The strongest interactions were seen with the SH2−SH3 adapter proteins Grb2 and Nck. The repeat sequence itself is not essential in this interaction. The data presented indicate that the different SH3 domains in the adapter proteins interact in a cooperative fashion with two distinct sites immediately upstream and downstream from the repeat sequence. Removal of all the putative SH3 binding domains in the third intracellular loop of the dopamine D4 receptor resulted in a receptor that could still bind spiperone and dopamine. Dopamine could not modulate the coupling of these mutant receptors to adenylyl cyclase and MAPK, although dopamine modulated receptor−G protein interaction appeared normal. The receptor deletion mutants show strong constitutive internalization that may account for the deficiency in functional activation of second messengers. The data indicates that the D4 receptor contains SH3 binding sites and that these sites fall within a region involved in the control of receptor internalization.

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“…[5][6][7] Unlike many neurotransmitters, DA is capable of exerting both stimulatory and inhibitory effects depending on receptor subtype involvement. [8][9][10] Thus, in the case of D 1 -like receptors, which include the D 1 -and D 5 -receptor subtypes, the amine acts as a stimulator in many biological systems while exerting 4 -receptor subtypes. Increasing evidence now suggests that subtypes of the DA receptor are differentially expressed in various regions of the brain.…”

Section: Introductionmentioning

confidence: 99%