TY - JOUR T1 - Constitutive Activity of Histamine H<sub>3</sub> Receptors Stably Expressed in SK-N-MC Cells: Display of Agonism and Inverse Agonism by H<sub>3</sub> Antagonists JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 908 LP - 914 VL - 299 IS - 3 AU - Kerstin Wieland AU - Gerold Bongers AU - Yumiko Yamamoto AU - Takeshi Hashimoto AU - Atsushi Yamatodani AU - Wiro M. B. P. Menge AU - Henk Timmerman AU - Timothy W. Lovenberg AU - Rob Leurs Y1 - 2001/12/01 UR - http://jpet.aspetjournals.org/content/299/3/908.abstract N2 - Agonist-independent activity of G-protein-coupled receptor, also referred to as constitutive activity, is a well-documented phenomenon and has been reported recently for both the histamine H1and H2 receptors. Using SK-N-MC cell lines stably expressing the human and rat H3 receptors at physiological receptor densities (500–600 fmol/mg of protein), we show that both the rat and human H3 receptors show a high degree of constitutive activity. The forskolin-mediated cAMP production in SK-N-MC cells is inhibited strongly upon expression of the Gi-coupled H3 receptor. The cAMP production can be further inhibited upon agonist stimulation of the H3receptor and can be enhanced by a variety of H3 antagonists acting as inverse agonists at the H3 receptor. Thioperamide, clobenpropit, and iodophenpropit raise the cAMP levels in SK-N-MC cells with potencies that match their receptor binding affinities. Surprisingly, impentamine and burimamide act as effective H3 agonists. Modification of the amine group of impentamine dramatically affected the pharmacological activity of the ligand. Receptor affinity was reduced slightly for most impentamine analogs, but the functional activity of the ligands varied from agonist to neutral antagonist and inverse agonist, indicating that subtle changes in the chemical structures of impentamine analogs have major impact on the (de)activation steps of the H3 receptor. In conclusion, upon stable expression of the rat and human H3 receptor in SK-N-MC cells constitutive receptor activity is detected. In this experimental system, H3 receptors ligands, previously identified as H3 antagonists, cover the whole spectrum of pharmacological activities, ranging from full inverse agonists to agonists. The American Society for Pharmacology and Experimental Therapeutics ER -