TY - JOUR T1 - Protean Agonism at α<sub>2A</sub>-Adrenoceptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 963 LP - 968 VL - 53 IS - 5 AU - Christian C. Jansson AU - Jyrki P. Kukkonen AU - Johnny Näsman AU - Ge Huifang AU - Siegfried Wurster AU - Raimo Virtanen AU - Juha-Matti Savola AU - Vic Cockcroft AU - Karl E. O. Åkerman Y1 - 1998/05/01 UR - http://molpharm.aspetjournals.org/content/53/5/963.abstract N2 - The coupling of the endogenously expressed α2A-adrenoceptors in human erythroleukemia cells (HEL 92.1.7) to Ca2+ mobilization and inhibition of forskolin-stimulated cAMP production was investigated. The two enantiomers of medetomidine [(±)-[4-(1-[2,3-dimethylphenyl]ethyl)-1H-imidazole]HCl] produced opposite responses. Dexmedetomidine behaved as an agonist in both assays (i.e., it caused Ca2+ mobilization and depressed forskolin-stimulated cAMP production). Levomedetomidine, which is a weak agonist in some test systems, reduced intracellular Ca2+ levels and further increased forskolin-stimulated cAMP production and therefore can be classified as an inverse agonist. A neutral ligand, MPV-2088, antagonized responses to both ligands. Several other, chemically diverse α2-adrenergic ligands also were tested. Ligands that could promote increases in Ca2+ levels and inhibition of cAMP production could be classified as full or partial agonists. Their effects could be blocked by the α2-adrenoceptor antagonist rauwolscine and by pertussis toxin treatment. Some typical antagonists such as rauwolscine, idazoxan, and atipamezole had inverse agonist activity like levomedetomidine. The results suggest that the α2A-adrenoceptors in HEL 92.1.7 cells exist in a precoupled state with pertussis toxin-sensitive G proteins, resulting in a constitutive mobilization of intracellular Ca2+ and inhibition of cAMP production in the absence of agonist. This constitutive activity can be antagonized by inverse agonists such as levomedetomidine and rauwolscine. Levomedetomidine can be termed a “protean agonist” because it is capable of activating uncoupled α2-adrenoceptors in other systems and inhibiting the constitutive activity of precoupled α2-adrenoceptors in HEL 92.1.7 cells. With this class of compounds, the inherent receptor “tone” could be adjusted, which should provide a new therapeutic principle in receptor dysfunction. The American Society for Pharmacology and Experimental Therapeutics ER -