Differential ion current activation by human 5-HT1A receptors in Xenopus oocytes : Evidence for agonist-directed trafficking of receptor signalling

Abstract The subject of the present study was the functional and pharmacological characterization of human 5-HT 1A receptor regulation of ion channels in Xenopus oocytes. Activation of the heterologously expressed human 5-HT 1A receptor induced two distinct currents in Xenopus oocytes, consisting of a smooth inward current ( I smooth ) and an oscillatory calcium-activated chloride current, I Cl(Ca) . 5-HT 1A receptor coupling to both ionic responses as well as to co-expressed inward rectifier potassium (GIRK) channels was pharmacologically characterized using 5-HT 1A receptor agonists. The relative order of efficacy for activation of GIRK current was 5-HT ≈ F13714 ≈ L694,247 ≈ LY228,729 > flesinoxan ≈ (±)8-OH-DPAT. In contrast, flesinoxan and (±)8-OH-DPAT typically failed to activate I Cl(Ca) . The other ligands behaved as full or partial agonists, exhibiting an efficacy rank order of 5-HT ≈ L694,247 > F13714 ≈ LY228,729. The pharmacological profile of I smooth activation was completely distinct: flesinoxan and F13714 were inactive and rather exhibited an inhibition of this current. I smooth was activated by the other agonists with an efficacy order of L694,247 > 5-HT ≈ LY228,729 > (±)8-OH-DPAT. Moreover, activation of I smooth was not affected by application of pertussis toxin or the non-hydrolyzable GDP-analogue, guanosine-5′- O -(2-thio)-diphosphate (GDPβS), suggesting a GTP binding protein-independent pathway. Together, these results suggest the existence of distinct and agonist-specific signalling states of this receptor.