title: Direct activation by dopamine of recombinant human 5-HT1A receptors: comparison with human 5-HT2C and 5-HT3 receptors.
abstract: The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT1A, 5-HT2C, and 5-HT3) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC50 values of 4.2 nM and 11.2 microM. Maximal responses induced by DA were 85 +/- 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT1A antagonist, WAY-100635 (50 nM). In CHO-K1 cells expressing 5-HT1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [3H]-8-OH-DPAT with IC50 values of 10.2 nM and 1.4 microM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 microM. Magnitudes of maximal DA induced currents were 42 +/- 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 microM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 microM and 266.3 microM. Maximal DA induced currents were 37 +/- 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 microM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT3 > 5-HT1A > 5-HT2C, and relative efficacy increased in the order of 5-HT1A > 5-HT2C > 5-HT3. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors.
authors.affiliation: Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, DHHS, Intramural Research Program, Baltimore, Maryland 21224, USA. moz@intra.nida.nih.gov
authors.forename: Murat
authors.initials: M
authors.lastname: Oz
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rotondo
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D002614:Chelating Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections / Q000379:methods; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013134:Spiperone / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D002614:Chelating Agents; D018492:Dopamine Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007191:Indazoles; D010879:Piperazines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines; D012333:RNA, Messenger; D044348:Receptors, Serotonin, 5-HT2; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013873:Thionucleotides; D014326:Tropanes; D044282:Receptor, Serotonin, 5-HT1A; C061531:LY 278584; D006153:Guanosine Diphosphate; D005576:Colforsin; D000077489:Piperazine; D012701:Serotonin; D013134:Spiperone; D004533:Egtazic Acid; C023427:guanosine 5'-O-(2-thiodiphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D006220:Haloperidol; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D004298:Dopamine