Structure and function of dopamine receptors

https://doi.org/10.1016/S0149-7634(99)00063-9Get rights and content

Abstract

Dopamine (DA) is the most abundant catecholamine in the brain. The involvement and importance of DA as a neurotransmitter in the regulation of different physiological functions in the central nervous system (CNS) is well known. Deregulation of the dopaminergic system has been linked with Parkinson's disease, Tourette's syndrome, schizophrenia, attention deficit hyperactive disorder (ADHD) and generation of pituitary tumours. This review focuses on the pharmacological and biochemical features shared by the dopamine receptors. We address their coupling to secondary messenger pathways and their physiological function based upon studies using pharmacological tools, specific brain lesions and, more recently, genetically modified animal models.

Section snippets

Dopamine

Dopamine (DA) belongs to a group of neurotransmitters called catecholamines. Their distinctive structural features are the single amine group, a nucleus of catechol (a benzene ring with two adjacent hydroxyl groups) and a side chain of ethylamine or one of its derivatives [1]. The precursor for the synthesis of DA is the aromatic amino acid tyrosine. Two reactions transform tyrosine into DA: the first is catalysed by the enzyme tyrosine hydroxylase (TH) which converts tyrosine into l

Dopamine receptors

Dopamine exerts its action by binding to specific membrane receptors [10], which belong to the family of seven transmembrane domain (7TM) G-protein coupled receptors. Five distinct dopamine receptors (DA-Rs) have been isolated, characterized and subdivided into two subfamilies, D1- and D2-like, on the basis of their biochemical and pharmacological properties. The D1-like subfamily comprises D1- and D5-R, while the D2-like includes D2-, D3- and D4-R. The C-terminus in both subfamilies contains

Dopamine receptor genes

Among DA-Rs, the rat D2-R cDNA was the first to be isolated [14]. This original cDNA clone contains an open reading frame of 1245 nucleotides encoding a protein of 415 residues, later called D2S (D2 short), with a typical D2 pharmacological profile. Later, several groups cloned a splice variant of this receptor, D2L (D2 long), from different species (rat, mouse, bovine, human, xenopus [15], [16], [17], [18], [19] and tissues (brain, pituitary and retina). The D2-R gene is composed of eight

Dopamine receptor expression

The D1- and D2-R genes have the most widespread and highest levels of expression of the DA receptors. D1-R is mainly expressed in the CP, nucleus accubens (Acb), OT, cerebral cortex (Cx) and amygdala [20]. In addition, D1 receptors have been detected also in the island of Calleja and in the subthalamic nucleus [20]. In the substantia nigra pars reticulata altough the binding of D1-R specific ligands has been shown, no mRNA has been detected. This seems to suggest that D1-R is synthesized in

Signal transduction pathways

The signal transduction pathways activated by DA-Rs are numerous. However, the best-described effects mediated by DA are the activation or inhibition of the cAMP pathway and modulation of Ca2+ signaling.

The stimulation of cellular effectors from DA receptors is mediated via the interaction with members of the heterotrimeric GTP-binding proteins [34]. The IL3 region of different DA receptors has been prove to play a pivotal role in the interaction with G-proteins [35]. In our laboratory, we have

Dopamine and locomotion

The importance of DA in the control of movements is well demonstrated in pathological conditions such as Parkinson's disease. Indeed, this disease is characterized by a strong reduction of circulating DA due to the degeneration of dopaminergic neurons [3], [4]. The availability of DA-R agonists and antagonists has permitted studies, which address the role of DA receptors in motor functions, such as forward locomotion, rearing, catalepsy, sniffing and grooming in mice or rats. Generally,

Conclusions

The understanding of the function of each dopamine receptor has been greatly improved by the generation of knock-out animals. Indeed, this approach has allowed the dissection of many key components of the dopaminergic system. Although many questions have been answered, many others still remain. Future studies combining different mutants and/or pharmacological treatments hopefully will help to establish the intricacies connection of the dopaminergic system and to better understand its function.

Acknowledgements

The authors thank Dr N.S. Foulkes and J.R.C. Parkinson for discussions. This work was supported by grants from the Institut de la Santé et de la Reeherche Médicale, the Centre National de la Recherche Scientifique, the Centre Hospitalier Universitaire Régional, the Association pour la Recherce sur le Cancer to E.B., and fellowships from the European Community (TMR Program, Marie Curie) to D.V., and Association France Parkinson to R.P.

References (87)

  • J.R Hepler et al.

    G proteins

    Trends Biochem Sci

    (1992)
  • J Guiramand et al.

    Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins

    J Biol Chem

    (1995)
  • E.J Choi et al.

    The regulatory diversity of the mammalian adenylyl cyclases

    Curr Opin Cell Biol

    (1993)
  • P.S Taraskevich et al.

    Dopamine (D2) or gamma-aminobutyric acid (GABAB) receptor activation hyperpolarizes rat melanotrophs and pertussis toxin blocks these responses and the accompanying fall in [Ca2+]i

    Neurosci Lett

    (1990)
  • D Piomelli

    Arachidonic acid in cell signaling

    Curr Opin Cell Biol

    (1993)
  • M.E Meyer et al.

    Effects of dopamine D1 antagonists SCH23390 and SK&F83566 on locomotor activities in rats

    Pharmacol Biochem Behav

    (1993)
  • M Xu et al.

    Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses

    Cell

    (1994)
  • M Rubinstein et al.

    Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine

    Cell

    (1997)
  • K Svensson et al.

    Behavioral and neurochemical data suggest functional differences between dopamine D2 and D3 receptors

    Eur J Pharmacol

    (1994)
  • M.P Carey et al.

    Differential distribution, affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model of ADHD

    Behav Brain Res

    (1998)
  • R.A Wise

    Neurobiology of addiction

    Curr Opin Neurobiol

    (1996)
  • J Drago et al.

    D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum

    Neuroscience

    (1996)
  • G Draisci et al.

    Temporal analysis of increases in c-fos, preprodynorphin and preproenkephalin mRNAs in rat spinal cord

    Brain Res Mol Brain Res

    (1989)
  • R.S Feldman et al.

    Catecholamines

    (1997)
  • C.R Gerfen

    The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia

    Annu Rev Neurosci

    (1992)
  • A.E Lang et al.

    Parkinson's disease. First of two parts

    N Engl J Med

    (1998)
  • A.E Lang et al.

    Parkinson's disease. Second of two parts

    N Engl J Med

    (1998)
  • M Le Moal et al.

    Mesocorticolimbic dopaminergic network: functional and regulatory roles

    Physiol Rev

    (1991)
  • G.F Koob et al.

    Cellular and molecular mechanisms of drug dependence

    Science

    (1988)
  • W Doppler

    Regulation of gene expression by prolactin

    Rev Physiol Biochem Pharmacol

    (1994)
  • J.A Gingrich et al.

    Recent advances in the molecular biology of dopamine receptors

    Annu Rev Neurosci

    (1993)
  • M.D Bates et al.

    Regulation of responsiveness at D2 dopamine receptors by receptor desensitization and adenylyl cyclase sensitization

    Mol Pharmacol

    (1991)
  • L Journot et al.

    An islet activating protein-sensitive G protein is involved in dopamine inhibition of angiotensin and thyrotropin-releasing hormone-stimulated inositol phosphate production in anterior pituitary cells

    J Biol Chem

    (1987)
  • J.R Bunzow et al.

    Cloning and expression of a rat D2 dopamine receptor cDNA [see comments]

    Nature

    (1988)
  • C.L Chio et al.

    A second molecular form of D2 dopamine receptor in rat and bovine caudate nucleus

    Nature

    (1990)
  • R Dal Toso et al.

    The dopamine D2 receptor: two molecular forms generated by alternative splicing

    EMBO J

    (1989)
  • B Giros et al.

    Alternative splicing directs the expression of two D2 dopamine receptor isoforms

    Nature

    (1989)
  • L.A Kukstas et al.

    Different expression of the two dopaminergic D2 receptors, D2415 and D2444, in two types of lactotroph each characterised by their response to dopamine, and modification of expression by sex steroids

    Endocrinology

    (1991)
  • B Grima et al.

    Complete coding sequence of rat tyrosine hydroxylase mRNA

    Proc Natl Acad Sci USA

    (1985)
  • H.H Van Tol et al.

    Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine

    Nature

    (1991)
  • T.V Beischlag et al.

    The human dopamine D5 receptor gene: cloning and characterization of the 5′-flanking and promoter region

    Biochemistry

    (1995)
  • M.T Minowa et al.

    Characterization of the 5( flanking region of the human D1A dopamine receptor gene

    Proc Natl Acad Sci USA

    (1992)
  • O Valdenaire et al.

    Transcription of the rat dopamine-D2-receptor gene from two promoters

    Eur J Biochem

    (1994)
  • Cited by (620)

    View all citing articles on Scopus
    View full text