Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes.
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.
Wedemeyer
Carolina
C
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Goutman
Juan D
JD
Avale
María E
ME
Franchini
Lucía F
LF
Rubinstein
Marcelo
M
Calvo
Daniel J
DJ
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D004594:Electrophysiology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D009638:Norepinephrine / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011110:Polymorphism, Genetic; D050638:Receptors, Dopamine D4 / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D014982:Xenopus laevis
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D050638:Receptors, Dopamine D4; D012701:Serotonin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D004298:Dopamine; D009638:Norepinephrine