κ-opioid receptor agonist inhibits the cholera toxin-sensitive G protein in the heart

Abstract

To explore the signaling mechanisms of the negative modulation of β-adrenoceptors by κ-opioid receptors (κ-OR) in the heart, the possibility of the interaction at the level of G protein and receptor was determined. Cholera toxin, an activator of the stimulatory G protein (Gs), elevated electrically induced intracellular Ca2+ ([Ca2+]i) transients and induced ribosylation of the α-subunit of Gs (Gsα) in rat ventricular myocytes. The effects were significantly attenuated by U50,488H, a specific agonist of κ-OR, and were abolished by nor-binaltorphimine, a selective κ-OR antagonist. The content of Gsα, however, was not affected by U50,488H. Receptor binding experiments showed that neither Bmax nor Kd of the binding of [3H]CGP-12177, a β-adrenoceptor antagonist, was affected by U50,488H. The current study provides the first evidence that κ-OR stimulation inhibits the ribosylation of the α-subunit of the Gs protein, thus inhibiting the action of cholera toxin on the protein.