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 μM. 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 μM). 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 μM, 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 μM. Magnitudes of maximal DA induced currents were 42 ± 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 μM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 μM and 266.3 μM. Maximal DA induced currents were 37 ± 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 μM). 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.