Differential ion current activation by human 5-HT_1A receptors in Xenopus oocytes: Evidence for agonist-directed trafficking of receptor signalling

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• 作者：Peter Heusler ; Petrus J. Pauwels ; Thierry Wurch ; Adrian Newman-Tancredi ; Jan Tytgat ; Francis C. Colpaert and Didier Cussac
• 关键词：GPCR ; 5-HT_1A receptor ; Agonist trafficking ; Electrophysiology ; Xenopus oocytes
• 刊名：Neuropharmacology
• 出版年：2005
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：2005
• 卷：49
• 期：7
• 页码：963-976
• 文件大小：499 K

摘要

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.