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Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2007 May 21; Vol. 562 (3), pp. 165-73. Date of Electronic Publication: 2007 Feb 08. - Publication Year :
- 2007
-
Abstract
- We studied the functional activation of different polymorphic variants of the human dopamine D(4) receptors by the three major central monoamines, dopamine, noradrenaline and serotonin. Dopamine D(4) receptors carrying two (D4.2), four (D4.4) or seven (D4.7) repeats within the third intracellular domain were co-expressed with G protein-regulated inwardly rectifying potassium channels (GIRK1) in frog oocytes. All the dopamine D(4) receptor variants coupled to oocyte G(i/o) proteins and modulated co-expressed GIRK1 channels. Monoamine-induced responses were detected as increases in voltage-clamp recorded GIRK1 currents. Dopamine, noradrenaline as well as serotonin stimulated dopamine D(4) receptors. Dose-response analysis showed that dopamine and noradrenaline are full agonists whereas serotonin acted as partial agonist. Dopamine was 5-fold more potent on D4.2 and D4.7 (EC(50)=1 nM) than on D4.4 (EC(50)=5 nM) suggesting that the actions of dopamine and therapeutic drugs on dopamine D(4) receptors might vary among individuals depending on their repertoire of expressed alleles. In contrast, noradrenaline and serotonin did not discriminate among dopamine D(4) receptor variants (EC(50 NA)=50 nM, EC(50 5-HT)=1.5 microM). All monoamine effects were blocked by the specific dopaminergic D(4) antagonist (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (PNU101387). Sequence analyses of dopamine D(4) receptors and related monoamine receptors revealed that dopamine D(4) receptors have most aminoacidic residues necessary for binding of dopamine, noradrenaline and serotonin. Our data indicate that dopamine D(4) receptors can be pharmacologically stimulated by any the three major central monoamines.
- Subjects :
- Alleles
Amino Acid Sequence
Animals
Dose-Response Relationship, Drug
Drug Delivery Systems
Drug Design
Electrophysiology
Female
G Protein-Coupled Inwardly-Rectifying Potassium Channels
GTP-Binding Protein alpha Subunits, Gi-Go metabolism
Humans
Oocytes drug effects
Oocytes metabolism
Polymorphism, Genetic
Receptors, Dopamine D4 metabolism
Xenopus laevis
Dopamine pharmacology
Norepinephrine pharmacology
Receptors, Dopamine D4 drug effects
Serotonin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 562
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17350612
- Full Text :
- https://doi.org/10.1016/j.ejphar.2007.01.055