Mutation S363A in the human δ-opioid receptor selectively reduces down-regulation by a peptide agonist

Abstract Chemically distinct opioid agonists have different abilities to down-regulate opioid receptors. The present study investigated the role of Ser 363 in human δ-opioid receptor down-regulation by a δ-selective peptide- and non-peptide agonist. Cyclic[ d -Pen 2 , d -Pen 5 ]enkephalin (DPDPE)-mediated down-regulation was significantly attenuated by a S363A mutation. In contrast, this mutation had no effect on down-regulation by (+)-4-[(α R )-α-((2 S ,5 R )-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl] N , N -diethylbenzamide (SNC80). These results demonstrate that the molecular mechanism of the human δ-opioid receptor down-regulation is agonist-specific.