The Mechanism of Changes in Adrenoceptor-Mediated Responses

Abstract

Quantitative and qualitative changes in adrenoceptors under various conditions were studied by binding experiments. Chronic treatment with reserpine increased the level of α₂-adrenoceptors in rat vas deferens and hypoxia increased the level of α₁-adrenoceptors in rat cardiomyocytes. Adenosine receptor agonists increased the affinity of the α₂-adrenoceptor in rat vas deferens for the agonist with an increase in receptor-mediated responses. Thus two types of changes in receptor binding sites were observed. Next, changes in the GTP-binding (G) protein were studied. Activation of cyclic AMP-dependent protein kinase (PKA) decreased the ADP-ribosylation of Gi (41 K) protein by islet-activating protein (pertussis toxin, IAP). Purified Gi protein was phosphorylated by the enzyme. IAP-sensitive G protein-mediated coupling responses such as phosphatidylinositol turnover in differentiated HL-60 cells were also modified under this condition. These results indicated that phosphorylation of GI by PKA caused a qualitative change of Gi. Lithium ions also decreased the ADP-ribosylation of GI by IAP. Then it determined if the decrease was accompanied with a dissociation of the subunits of Gi. Phosphorylation of Gi by PKA impaired the dissociation of the subunits of GI caused by Mg²⁺ and GTPγS, wheareas lithium ions did not have any effect on their dissociation. Thus some conditions caused a functional change in the so-called “qualitative change” of Gi.