RT Journal Article
SR Electronic
T1 The Attenuation of Epinephrine-Dependent Adenylate Cyclase by Adenosine and the Characteristics of the Adenosine Stimulatory and Inhibitory Sites
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 737
OP 748
VO 16
IS 3
A1 SERGEI BRAUN
A1 ALEXANDER LEVITZKI
YR 1979
UL http://molpharm.aspetjournals.org/content/16/3/737.abstract
AB Turkey erythrocyte and rat caudate adenylate cyclase [ATP pyrophosphatase-lyase (cyclizing) EC 4.6.1.1] respond to β-receptor adenergic agents and to adenosine agonists. In both systems single adenylate cyclase responds to the two receptors. In both tissues the effect of the two agonists is not additive and the enzyme can be activated only by one agonist at a time. The adenosine receptor is permanently coupled to the adenylate cyclase moiety and therefore the portion of the enzyme that is in its active form is directly proportional to the degree of saturation of adenosine sites. In contrast, the β-receptor is not coupled to the enzyme and activates the latter by a biomolecular collision between the two species that occurs during the diffusion of the hormone bound β-receptor. It follows that increasing concentrations of adenosine strongly enlarge the part of cyclase molecules governed by the adenosine receptor and, accordingly, reduce the free enzyme pool, accessible to β-receptor agonists, whereas hormone-occupied β-receptor cannot influence the pool of adenylate cyclase accessible to the adenosine receptor. Hence at saturating concentrations of adenosine only the adenosine-induced activity will be expressed and the combined effect of the two ligands is independent of β-agonist concentration. In turkey erythrocyte adenylate cyclase adenosine is a much poorer agonist than a β-agonist. Therefore, increasing adenosine concentrations inhibit β-agonist-stimulated cAMP production. The caudate nucleus adenylate cyclase presents a diametrically opposite situation where adenosine is a more potent agonist than epinephrine and thus, in the presence of adenosine, cAMP production is increased above that achieved by β-agonists. Caudate nucleus cyclase but not turkey erythrocyte cyclase possesses also an adenosine inhibitory site distinct from the stimulatory site. The ligand specificities of these two types of adenosine sites are different. The possible physiological role of the adenosine-induced modulation of hormonal response is discussed.