Abstract

The coupling of the endogenously expressed α_2A-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 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 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.