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Title: Differential ion current activation by human 5-HT(1A) receptors in Xenopus oocytes: evidence for agonist-directed trafficking of receptor signalling
Authors: Heusler, Peter ×
Pauwels, Petrus J
Wurch, Thierry
Newman-Tancredi, Adrian
Tytgat, Jan
Colpaert, Francis C
Cussac, Didier #
Issue Date: Dec-2005
Series Title: Neuropharmacology vol:49 issue:7 pages:963-76
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.
URI: 
ISSN: 0028-3908
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Toxicology and Pharmacology
× corresponding author
# (joint) last author

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