Occupancy-response relationships for beta- and alpha 2-adrenergic receptors exerting opposing effects on cAMP production.
In primary glial cultures, norepinephrine (NE) activates both beta-adrenergic receptors to increase cAMP formation and alpha 2-adrenergic receptors to partially inhibit this response. We used selective alkylating agents to compare the concentration-dependence and receptor reserves for activation of each subtype. Partial inactivation of beta-receptors with alkylating pindolol (BIM) caused a slight decrease in the potency of isoproterenol (ISO) in increasing cAMP accumulation and a progressive decrease in maximum response. The KA for ISO was 9.8 +/- 2 nM, with a 2-3-fold beta-receptor reserve. BIM pretreatment decreased the maximal response to NE without significantly altering its apparent EC50 (41 +/- 6.7 nM). Partial inactivation of alpha 2-adrenergic receptors with EEDQ increased the maximal response to NE without significantly altering its apparent EC50 (41 +/- 6.2 nM). NE inhibited the cAMP response to ISO with an apparent EC50 of 38 +/- 1.2 nM. EEDQ pretreatment reduced inhibition of the ISO response by both NE and the alpha 2-agonist UK 14,304, and inhibition of the forskolin response by UK 14,304. EEDQ pretreatment caused only a small decrease in potency for the alpha 2-agonists. The KA for NE in inhibiting the ISO response was 120 +/- 30 nM, indicating a 2-3-fold alpha 2-receptor reserve. These results suggest that NE has similar affinities and receptor reserves for beta- and alpha 2-adrenergic receptors in this system, and activates and inhibits adenylate cyclase at the same agonist concentrations.
Atkinson
B N
BN
Department of Pharmacology, Emory University Medical School, Atlanta, GA 30322.
Minneman
K P
KP
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; C000470:EEDQ; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine