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CELLULAR AND MOLECULAR

Ca²⁺ Responses in Chinese Hamster Ovary-K1 Cells Demonstrate an Atypical Pattern of Ligand-Induced 5-HT_1A Receptor Activation

Centre de Recherche Pierre Fabre, Department of Cellular and Molecular Biology, Castres, France

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-HT_1A autoreceptors than at postsynaptic 5-HT_1A receptors. The present study investigated Ca²⁺ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT_1A receptor by 5-HT, prototypical 5-HT_1A 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-HT_1A receptors. 5-HT (pEC₅₀ = 6.70 ± 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca²⁺ response. High-magnitude Ca²⁺ responses (E_max, 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-HT_1A 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-HT_1A 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]GTPS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT_1A receptor. Remarkably, differences between ligands that seem small in the [³⁵S]GTPS binding assay translate into huge differences in the magnitude of Ca²⁺ responses. Therefore, some of these 5-HT_1A 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-HT_1A receptor ligands seems to be codetermined by the effector pathway.

Address correspondence to: Dr. Petrus J. Pauwels, Centre d'Immunologie Pierre Fabre, 5, avenue Napoléon III-BP 497, F 74164 Saint-Julien-en-Genevois Cedex, France. E-mail: peter.pauwels{at}pierre-fabre.com

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