title: Differential ion current activation by human 5-HT(1A) 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 approximately F 13714 approximately L 694,247 approximately LY 228,729>flesinoxan approximately (+/-)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 approximately L 694,247>F 13714 approximately LY 228,729. The pharmacological profile of I(smooth) activation was completely distinct: flesinoxan and F 13714 were inactive and rather exhibited an inhibition of this current. I(smooth) was activated by the other agonists with an efficacy order of L 694,247>5-HT approximately LY 228,729>(+/-)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 (GDP betaS), suggesting a GTP binding protein-independent pathway. Together, these results suggest the existence of distinct and agonist-specific signalling states of this receptor.
authors.affiliation: Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, F-81106 Castres Cedex, France. peter.heusler@pierre-fabre.com
authors.forename: Peter
authors.initials: P
authors.lastname: Heusler
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: Thierry
authors.initials: T
authors.lastname: Wurch
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.forename: Francis C
authors.initials: FC
authors.lastname: Colpaert
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D000818:Animals; D065101:Chloride Channel Agonists; D004594:Electrophysiology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000819:agonists*; D008024:Ligands; D009154:Mutation; D009865:Oocytes; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D065101:Chloride Channel Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007473:Ion Channels; D008024:Ligands; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D013873:Thionucleotides; D044282:Receptor, Serotonin, 5-HT1A; D006153:Guanosine Diphosphate; D012701:Serotonin; D012313:RNA; C023427:guanosine 5'-O-(2-thiodiphosphate); D037342:Pertussis Toxin