PT - JOURNAL ARTICLE AU - Petrus J. Pauwels AU - Francis C. Colpaert TI - Ca<sup>2+</sup> Responses in Chinese Hamster Ovary-K1 Cells Demonstrate an Atypical Pattern of Ligand-Induced 5-HT<sub>1A</sub> Receptor Activation AID - 10.1124/jpet.103.055871 DP - 2003 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 608--614 VI - 307 IP - 2 4099 - http://jpet.aspetjournals.org/content/307/2/608.short 4100 - http://jpet.aspetjournals.org/content/307/2/608.full SO - J Pharmacol Exp Ther2003 Nov 01; 307 AB - Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 ± 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 ± 4), 5-carboxamidotryptamine (100 ± 3), and F 14679 (87 ± 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (≤5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5′-O-(3-[35 S]thio)triphosphate ([35S]GTPγS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPγS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway. The American Society for Pharmacology and Experimental Therapeutics