Effects of endogenous redox-active compounds on coupling of human beta 2-adrenergic receptors.
Altered redox states such as metabolic acidosis may impair beta-adrenergic receptor responsiveness. Beta-adrenergic receptor function requires formation of a high affinity, "coupled" state of the receptor. The degree of coupling is reflected in the ratio of dissociation constants, KL/KH, for the low and high affinity states of the receptor. It has previously been demonstrated that 16 mM lactate and pH 7.1 induce independent defects in beta-adrenergic receptor function. The purpose of this study was to examine further how endogenous redox agents might alter high affinity state formation. Normal neutrophil membrane preparations containing beta-adrenergic receptors were exposed to several concentrations of three redox couplets native to plasma: lactate (L)-pyruvate (P), beta-hydroxybutyrate (BOHB)-acetoacetate (AcAc), and glutathione (GSH-GSSG). BOHB, AcAc, and P had no isolated effect on high affinity state formation while 10 mM lactate diminished KL/KH by 30% (p less than 0.001). Dropping the pH from 7.4 to 7.1 resulted in a 50% to 70% reduction in KL/KH (p less than 0.001), independent of metabolite present. GSH or GSSG exposure resulted in a concentration-dependent fall in KL/KH value. Thus, high affinity state formation is regulated by redox couplets and pH independently. The reduced responsiveness of beta-adrenergic receptors observed in such states as metabolic acidosis could result from direct effects of redox couplets in addition to those of low pH.
D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates / Q000494:pharmacology; D000138:Acidosis / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D019803:Glutathione Disulfide; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006885:Hydroxybutyrates / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007773:Lactates / Q000494:pharmacology; D019344:Lactic Acid; D010084:Oxidation-Reduction; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D000090:Acetoacetates; D006885:Hydroxybutyrates; D007773:Lactates; D011773:Pyruvates; D011943:Receptors, Adrenergic, beta; D019344:Lactic Acid; C016635:acetoacetic acid; D019289:Pyruvic Acid; D005978:Glutathione; D007545:Isoproterenol; D020155:3-Hydroxybutyric Acid; D019803:Glutathione Disulfide