Protean Agonism at α2A-Adrenoceptors

• Published in: Molecular pharmacology 1998-05, Vol.53 (5), p.963
• Main Authors: Christian C. Jansson, Jyrki P. Kukkonen, Johnny Näsman, Ge Huifang, Siegfried Wurster, Raimo Virtanen, Juha-Matti Savola, Vic Cockcroft, Karl E. O. à kerman
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111

The coupling of the endogenously expressed α 2A -adrenoceptors in human erythroleukemia cells (HEL 92.1.7) to Ca 2+ mobilization and inhibition of forskolin-stimulated cAMP production was investigated. The two enantiomers of medetomidine [(±)-[4-(1-[2,3-dimethylphenyl]ethyl)-1 H -imidazole]HCl] produced opposite responses. Dexmedetomidine behaved as an agonist in both assays (i.e., it caused Ca 2+ mobilization and depressed forskolin-stimulated cAMP production). Levomedetomidine, which is a weak agonist in some test systems, reduced intracellular Ca 2+ 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 α 2 -adrenergic ligands also were tested. Ligands that could promote increases in Ca 2+ levels and inhibition of cAMP production could be classified as full or partial agonists. Their effects could be blocked by the α 2 -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 α 2A -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 Ca 2+ 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 α 2 -adrenoceptors in other systems and inhibiting the constitutive activity of precoupled α 2 -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.