title: Protean agonism at alpha2A-adrenoceptors.
abstract: The coupling of the endogenously expressed alpha2A-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 alpha2-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 alpha2-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 alpha2A-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 alpha2-adrenoceptors in other systems and inhibiting the constitutive activity of precoupled alpha2-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.
authors.affiliation: Department of Biochemistry and Pharmacy, Abo Akademi University, Turku, Finland.
authors.forename: C C
authors.initials: CC
authors.lastname: Jansson
authors.forename: J P
authors.initials: JP
authors.lastname: Kukkonen
authors.forename: J
authors.initials: J
authors.lastname: Näsman
authors.forename: G
authors.initials: G
authors.lastname: Huifang
authors.forename: S
authors.initials: S
authors.lastname: Wurster
authors.forename: R
authors.initials: R
authors.lastname: Virtanen
authors.forename: J M
authors.initials: JM
authors.lastname: Savola
authors.forename: V
authors.initials: V
authors.lastname: Cockcroft
authors.forename: K E
authors.initials: KE
authors.lastname: Akerman
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology; D008297:Male; D020926:Medetomidine; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C547768:ADRA2A protein, human; C547769:Adra2a protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D007192:Indenes; C108487:MPV 1743 AIII; D018341:Receptors, Adrenergic, alpha-2; D000242:Cyclic AMP; D020926:Medetomidine; D002118:Calcium