Structure and function of dopamine receptors
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.
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