Pertussis Toxin‐Insensitive Signaling of the ORL1 Receptor: Coupling to Gz and G16 Proteins

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Abstract
Nociceptin/OFQ is the endogenous ligand for the G protein‐coupled opioid receptor‐like (ORL1) receptor. To elucidate the cellular functions of the ORL1 receptor, we examined its ability to interact with Gz and G16, two pertussis toxin (PTX)‐insensitive G proteins that are known molecular partners for the opioid receptors. In HEK 293 cells transiently expressing the ORL1 and dopamine D1 receptors, nociceptin/OFQ dose‐dependently inhibited dopamine‐stimulated cyclic AMP (cAMP) accumulation in a PTX‐sensitive manner. However, PTX failed to block the nociceptin/OFQ‐induced inhibition of dopamine‐stimulated cAMP accumulation in HEK 293 cells co‐expressing the α‐subunit of Gz. This result indicates functional interaction between the ORL1 receptor and Gz. A similar result was obtained with retinoic acid‐differentiated SH‐SY5Y cells, which endogenously express both the ORL1 receptor and Gz. When the ORL1 receptor was transiently co‐expressed in COS‐7 cells with the α‐subunit of G16, nociceptin/OFQ dose‐dependently stimulated the formation of inositol phosphates. Nociceptin‐induced stimulation of phospholipase C was absolutely dependent on the co‐expression of α16 and exhibited the appropriate ligand selectivity. In terms of its ability to interact with PTX‐insensitive G proteins, the ORL1 receptor behaves very much like the opioid receptors.

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