Agonist trafficking of G i/o ‐mediated α 2A ‐adrenoceptor responses in HEL 92.1.7 cells

The ability of 19 agonists to elevate Ca 2+ and inhibit forskolin‐induced cyclic AMP elevation through α 2A ‐adrenoceptors in HEL 92.1.7 cells was investigated. Ligands of catecholamine‐like‐ (five), imidazoline‐ (nine) and non‐catecholamine‐non‐imidazoline‐type (five) were included. The relative maximum responses were similar in both assays. Five ligands were full or nearly full agonists, six produced 20 – 70% of the response to a full agonist and the remaining eight gave lower responses (<20%) so that their potencies were difficult to evaluate. Marked differences in the potencies of the agonists with respect to the two measured responses were seen. The catecholamines were several times less potent in decreasing cyclic AMP than in increasing Ca 2+ , whereas the other, both imidazoline and ox‐/thiazoloazepine ligands, were several times more potent with respect to the former than the latter response. For instance, UK14,304 was more potent than adrenaline with respect to the cyclic AMP response but less potent than adrenaline with respect to the Ca 2+ response. All the responses were sensitive to pertussis toxin‐pretreatment. Also the possible role of PLA 2 , β‐adrenoceptors or ligand transport or metabolism as a source of error could be excluded. The results suggest that the active receptor states produced by catecholamines and the other agonists are markedly different and therefore have different abilities to activate different signalling pathways.British Journal of Pharmacology (2001) 132 , 1477–1484; doi: 10.1038/sj.bjp.0703964