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Vol. 53, Issue 5, 963-968, May 1998

Protean Agonism at alpha 2A-Adrenoceptors

Christian C. Jansson, Jyrki P. Kukkonen, Johnny Näsman, Ge Huifang, Siegfried Wurster, Raimo Virtanen, Juha-Matti Savola, Vic Cockcroft, and Karl E. O. Åkerman

Department of Biochemistry and Pharmacy (C.C.J., J.P.K., G.H.), Turku Centre for Biotechnology (J.P.K.), Åbo Akademi University, Turku, Finland, Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland (C.C.J., G.H., S.W.), Department of Physiology and Medical Biophysics, Uppsala University, Uppsala, Sweden (J.P.K., K.E.O.A, J.N.), and Orion-Corporation, Orion-Pharma, Turku, Finland (S.W., R.V., J.-M.S., V.C.)

The coupling of the endogenously expressed alpha 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 alpha 2-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 alpha 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 alpha 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 alpha 2-adrenoceptors in other systems and inhibiting the constitutive activity of precoupled alpha 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.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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