Regulation of multiple effectors by the cloned delta-opioid receptor: stimulation of phospholipase C and type II adenylyl cyclase.

The delta-opioid receptor is known to regulate multiple effectors in various tissues. When expressed in human embryonic kidney 293 cells, the cloned delta-opioid receptor inhibited cyclic AMP (cAMP) accumulation in response to the delta-selective agonist [D-Pen2,D-Pen5]-enkephalin. The inhibitory response of [D-Pen2,D-Pen5]-enkephalin was dependent on the expression of the delta-opioid receptor and exhibited an EC50 of 1 nM. The receptor showed ligand selectivity and a pharmacological profile that is appropriate for the delta-opioid subtype. The inhibition was blocked by the opiate antagonist naloxone or by pretreatment of the cells with pertussis toxin. Co-transfection of the delta-opioid receptor with type II adenylyl cyclase and an activated mutant of alpha s converted the delta-opioid signal from inhibition to stimulation of cAMP accumulation. It is interesting that when transfected into Ltk-fibroblasts, the cloned delta-opioid receptor was able to stimulate the formation of inositol phosphates (EC50 = 8 nM). This response was sensitive to pertussis toxin. The opioid-mediated formation of inositol phosphates exhibited the same ligand selectivity as seen with the inhibition of cAMP accumulation. The ability of the delta-opioid receptor to couple to G proteins other than Gi was also examined. Cotransfection studies revealed that the delta-opioid receptor can utilize Gz to regulate cAMP accumulation and to stimulate the formation of inositol phosphates.