Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes
We studied the functional activation of different polymorphic variants of the human dopamine D4 receptors by the three major central monoamines, dopamine, noradrenaline and serotonin. Dopamine D4 receptors carrying two (D4.2), four (D4.4) or seven (D4.7) repeats within the third intracellular domain...
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todo:paper_00142999_v562_n3_p165_Wedemeyer2023-10-03T14:12:07Z Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes Wedemeyer, C. Goutman, J.D. Avale, M.E. Franchini, L.F. Rubinstein, M. Calvo, D.J. Dopamine D4 receptor GIRK channels Noradrenaline Polymorphic variants Serotonin dopamine dopamine 4 receptor dopamine receptor blocking agent G protein coupled inwardly rectifying potassium channel monoamine noradrenalin serotonin sonepiprazole allele animal cell article controlled study frog gene expression genetic polymorphism genetic variability ion current nonhuman oocyte priority journal protein domain protein expression receptor upregulation sequence analysis voltage clamp Xenopus laevis Alleles Amino Acid Sequence Animals Dopamine 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 Humans Norepinephrine Oocytes Polymorphism, Genetic Receptors, Dopamine D4 Serotonin Xenopus laevis We studied the functional activation of different polymorphic variants of the human dopamine D4 receptors by the three major central monoamines, dopamine, noradrenaline and serotonin. Dopamine D4 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 D4 receptor variants coupled to oocyte Gi/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 D4 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 (EC50 = 1 nM) than on D4.4 (EC50 = 5 nM) suggesting that the actions of dopamine and therapeutic drugs on dopamine D4 receptors might vary among individuals depending on their repertoire of expressed alleles. In contrast, noradrenaline and serotonin did not discriminate among dopamine D4 receptor variants (EC50 NA = 50 nM, EC50 5-HT = 1.5 μM). All monoamine effects were blocked by the specific dopaminergic D4 antagonist (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (PNU101387). Sequence analyses of dopamine D4 receptors and related monoamine receptors revealed that dopamine D4 receptors have most aminoacidic residues necessary for binding of dopamine, noradrenaline and serotonin. Our data indicate that dopamine D4 receptors can be pharmacologically stimulated by any the three major central monoamines. © 2007 Elsevier B.V. All rights reserved. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00142999_v562_n3_p165_Wedemeyer |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Dopamine D4 receptor GIRK channels Noradrenaline Polymorphic variants Serotonin dopamine dopamine 4 receptor dopamine receptor blocking agent G protein coupled inwardly rectifying potassium channel monoamine noradrenalin serotonin sonepiprazole allele animal cell article controlled study frog gene expression genetic polymorphism genetic variability ion current nonhuman oocyte priority journal protein domain protein expression receptor upregulation sequence analysis voltage clamp Xenopus laevis Alleles Amino Acid Sequence Animals Dopamine 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 Humans Norepinephrine Oocytes Polymorphism, Genetic Receptors, Dopamine D4 Serotonin Xenopus laevis |
| spellingShingle |
Dopamine D4 receptor GIRK channels Noradrenaline Polymorphic variants Serotonin dopamine dopamine 4 receptor dopamine receptor blocking agent G protein coupled inwardly rectifying potassium channel monoamine noradrenalin serotonin sonepiprazole allele animal cell article controlled study frog gene expression genetic polymorphism genetic variability ion current nonhuman oocyte priority journal protein domain protein expression receptor upregulation sequence analysis voltage clamp Xenopus laevis Alleles Amino Acid Sequence Animals Dopamine 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 Humans Norepinephrine Oocytes Polymorphism, Genetic Receptors, Dopamine D4 Serotonin Xenopus laevis Wedemeyer, C. Goutman, J.D. Avale, M.E. Franchini, L.F. Rubinstein, M. Calvo, D.J. Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| topic_facet |
Dopamine D4 receptor GIRK channels Noradrenaline Polymorphic variants Serotonin dopamine dopamine 4 receptor dopamine receptor blocking agent G protein coupled inwardly rectifying potassium channel monoamine noradrenalin serotonin sonepiprazole allele animal cell article controlled study frog gene expression genetic polymorphism genetic variability ion current nonhuman oocyte priority journal protein domain protein expression receptor upregulation sequence analysis voltage clamp Xenopus laevis Alleles Amino Acid Sequence Animals Dopamine 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 Humans Norepinephrine Oocytes Polymorphism, Genetic Receptors, Dopamine D4 Serotonin Xenopus laevis |
| description |
We studied the functional activation of different polymorphic variants of the human dopamine D4 receptors by the three major central monoamines, dopamine, noradrenaline and serotonin. Dopamine D4 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 D4 receptor variants coupled to oocyte Gi/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 D4 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 (EC50 = 1 nM) than on D4.4 (EC50 = 5 nM) suggesting that the actions of dopamine and therapeutic drugs on dopamine D4 receptors might vary among individuals depending on their repertoire of expressed alleles. In contrast, noradrenaline and serotonin did not discriminate among dopamine D4 receptor variants (EC50 NA = 50 nM, EC50 5-HT = 1.5 μM). All monoamine effects were blocked by the specific dopaminergic D4 antagonist (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (PNU101387). Sequence analyses of dopamine D4 receptors and related monoamine receptors revealed that dopamine D4 receptors have most aminoacidic residues necessary for binding of dopamine, noradrenaline and serotonin. Our data indicate that dopamine D4 receptors can be pharmacologically stimulated by any the three major central monoamines. © 2007 Elsevier B.V. All rights reserved. |
| format |
JOUR |
| author |
Wedemeyer, C. Goutman, J.D. Avale, M.E. Franchini, L.F. Rubinstein, M. Calvo, D.J. |
| author_facet |
Wedemeyer, C. Goutman, J.D. Avale, M.E. Franchini, L.F. Rubinstein, M. Calvo, D.J. |
| author_sort |
Wedemeyer, C. |
| title |
Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| title_short |
Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| title_full |
Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| title_fullStr |
Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| title_full_unstemmed |
Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes |
| title_sort |
functional activation by central monoamines of human dopamine d4 receptor polymorphic variants coupled to girk channels in xenopus oocytes |
| url |
http://hdl.handle.net/20.500.12110/paper_00142999_v562_n3_p165_Wedemeyer |
| work_keys_str_mv |
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1807318799357050880 |