Selective desensitization of beta 1- and beta 2-andrenergic receptors in C6 glioma cells. Effects on catecholamine responsiveness.

We studied the effects of changing beta 1- and beta 2-adrenergic receptor (AR) subtype ratios and densities on cyclic AMP (cAMP) responses to norepinephrine (NE) and epinephrine (EPI) in rat C6 glioma cells. Dexamethasone (DEX) increased beta 2- and decreased beta 1-AR expression without changing total beta-AR density, whereas pretreatment with selective agonists specifically downregulated each subtype. Combinations of these treatments produced cells with six different beta 2/beta 1 ratios that ranged from 0 (100% beta 1) to 2.85. We compared the effects of NE and EPI on cAMP accumulation in each condition and observed a predominantly beta 1 pharmacology (NE > EPI) under most conditions. However, as the beta 2-AR density exceeded the number of beta 1-ARs we observed a progressive shift toward a more beta 2-like pharmacology (EPI > NE), without the appearance of biphasic concentration-response curves. The ratio of beta 2/beta 1 density correlated significantly (p < 0.006) with the ratio of the potencies of NE and EPI in increasing cAMP formation. We conclude that in native C6 cells beta 1-ARs appear to couple more efficiently to cAMP accumulation than do beta 2-ARs, but both subtypes contribute to catecholamine responses in a nonadditive manner when the proportion of beta 2-ARs is increased.