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.
Guerrero
S W
SW
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zhong
H
H
Minneman
K P
KP
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D003907:Dexamethasone; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine