Agonist-regulated endocytosis and desensitization of the human nociceptin receptor

A series of nociceptin receptor ligands has been investigated in relationship to their capability to promote receptor endocytosis, desensitization (evaluated as inhibition of forskolin-stimulated cAMP production) and compensatory upregulation of adenylyl cyclase activity in CHO-KI cells expressing the cloned human nociceptin receptor. Nociceptin (NC), [Arg(14), Lys(15)]NC-NH2 and NNC 63-0532 (0.01 nM-10 mu M) induce a concentration-dependent endocytosis and recycling of the nociceptin receptor. This mechanism contributes to maintain receptor signaling as it counteracts desensitization development and enhances a compensatory upregulation of adenyl cyclase activity. In contrast, the partial agonists [Phe(1), Psi(CH2NH)Gly(2)]NC(1-13)-NH2, Ac-RYYRIK-NH2 and Ac-RYYRWK-NH2 (UP to 100 mu M) fail to induce receptor endocytosis and cause a pronounced receptor desensitization that is not influenced by monensin, a blocker of recycling of the internalized receptors.