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Altered Adrenergic Response and Specificity of the Receptors in Rat Ascites Hepatoma AH130

Third Division of the Research Laboratory for Development of Medicine, School of Pharmacy, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-11, Japan

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 AH130 cells but IPN > Epi > NE in hepatocytes. We then used the ₁-selective ligand [³H]prazosin, the ₂-selective ligand [³H]clonidine, and the ß-ligand [¹²⁵I]iodocyanopindolol ([¹²⁵I]ICYP), and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidine-binding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (K_i) of the ß₁-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the ß₂-selective agonist salbutamol for AH130 cells gave only one K_i value which was much higher than both high and low K_i values of the drug for hepatocytes. These findings indicate that the - and ß-adrenergic receptors in hepatocytes are predominantly ₁- type and ß₂-type, but that those in AH130 cells are predominantly ₂-type and ß₁-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of ₂-adrenergic receptors, linked with the inhibitory guanine-nucleotide binding regulatory protein, instead of ₁-adrenergic receptors, and ß₁-adrenergic receptors with low affinity for the hormone.

¹ To whom requests for reprints should be addressed.

Received 4/20/89. Revised 7/13/89. Accepted 8/17/89.