Occupancy-response relationships for beta- and alpha 2-adrenergic receptors exerting opposing effects on cAMP production

Receptor. Fall 1992;2(3):195-206.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / biosynthesis*
  • Isoproterenol / pharmacology
  • Kinetics
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Norepinephrine / pharmacology
  • Pindolol / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Receptors, Adrenergic, alpha / drug effects
  • Receptors, Adrenergic, alpha / metabolism*
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*

Substances

  • Adrenergic alpha-Antagonists
  • Quinolines
  • Receptors, Adrenergic, alpha
  • Receptors, Adrenergic, beta
  • Colforsin
  • EEDQ
  • Pindolol
  • Cyclic AMP
  • Isoproterenol
  • Norepinephrine