Altered Adrenergic Response and Specificity of the Receptors

Adenylate cyclase activation through adrenergic receptors in rat ascites hepatoma (AH) 130 cells in response to adrenergic drugs was studied, and receptor binding and displacement were compared with those of normal rat hepatocytes. Epinephrine (Epi) and norepinephrine (NE) activated AH130 adenylate cyclase about half as much as isoproterenol (IPN) but equaled IPN after treatment with the «-antagonist phentolamine or islet-activating protein (IAP). The three catecholamines in hepatocytes were similar regardless of phentolamine or IAP. These catecholamines activated adenylate cyclase in order of IPN > NE > Epi in AH 130 cells but IPN > Epi > NE in hepatocytes. We then used the ai-selective ligand [3H|prazosin, the a2-selective ligand [3H]clonidine, and the 0-ligand ['"IJiodocyanopindolol ([125I]ICYP),and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidinebinding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (A,) of the ^-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the /82-selective agonist salbutamol for AH130 cells gave only one K¡ value which was much higher than both high and low K¡ values of the drug for hepatocytes. These findings indicate that the aand /9-adrenergic receptors in hepa tocytes are predominantly a,type and /S2-type,but that those in AH130 cells are predominantly a2-type and 0,-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of a2adrenergic receptors, linked with the inhibitory guanine-nucleotide bind ing regulatory protein, instead of at-adrenergic receptors, and /<,-:ulrenergic receptors with low affinity for the hormone.