The ORL₁ Receptor: Molecular Pharmacology and Signalling Mechanisms

Abstract

The cloning of the opioid-receptor-like 1 (ORL₁) receptor and the identification of nociceptin as its endogenous agonist have revealed a new G-protein-coupled receptor signalling system. The structural and functional homology of ORL₁ to the opioid receptor systems has posed a number of challenges in understanding the often competing physiological responses elicited by these G-protein-coupled receptors. Thus, this review will attempt to summarize recent research by many groups that has revealed numerous subtleties of the ORL₁ receptor and its signalling pathways, as well as document the efforts to produce high-affinity selective ligands for the ORL₁ receptor that may be of value as research and therapeutic tools.

Nociceptin Receptor Impairs Recognition Memory via Interaction with NMDA Receptor-Dependent Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in the Hippocampus

“…Previous in vitro studies reported stimulatory actions of N/OFQ on ERK signaling pathways in cell lines transfected with NOP receptor (Fukuda et al, 1997;New and Wong, 2002). Here, we show that in living animals NOP receptor activation inhibits ERK pathway in the hippocampus.…”

“…NOP receptor is a G-protein-coupled receptor that negatively regulates the activity of adenylate cyclases, inhibits voltage-gated Ca 2ϩ channels and activates inward rectifying K ϩ channels. By blocking Ca 2ϩ current and inhibiting cAMP production (New and Wong, 2002), NOP receptor can suppress the activation of multiple cascades that ultimately converge on ERK, and thereby disrupts NMDA receptor-mediated recognition memory formation. In this regard, Mamiya et al (2003) have shown that NOP and NMDA receptors modulate in an opposing manner the activity of Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) in hippocampal slice.…”

“…Many neurotransmitter receptors which facilitate memory formation and promote synaptic plasticity, including the glutamatergic NMDA receptor, positively regulate ERK activity in hippocampal neurons (Poser and Storm, 2001;Sweatt, 2004). NOP receptor was also shown to activate this signaling pathway in transfected cell lines (Fukuda et al, 1997;New and Wong, 2002); however, no information is available with regard to its action in brain neurons. Based on behavioral and electrophysiological studies, we hypothesized that NOP receptor would rather inhibit ERK activity in hippocampal neurons during learning.…”

Modulation of Ca2+Channels by Opioid Receptor-Like 1 Receptors Natively Expressed in Rat Stellate Ganglion Neurons Innervating Cardiac Muscle

“…Because ORL1 receptors and opioid receptors, in general, are well established to couple to PTX-sensitive G␣ i/o protein subunits (New and Wong, 2002), we found that Ca 2ϩ channel inhibition was significantly decreased in SG neurons pretreated with the toxin. Similar findings have been previously published (Morikawa et al, 1998;Connor et al, 1999;Larsson et al, 2000;Beedle et al, 2004;Yeon et al, 2004).…”

“…ORL1 receptors are coupled to members of the pertussis toxin (PTX)-sensitive G␣ i/o G protein family. Stimulation of ORL1 receptors by Noc results in inhibition of voltage-gated Ca 2ϩ channels, activation of G protein-gated inwardly rectifying K ϩ channels, and negative coupling to adenylyl cyclases (for review, see New and Wong, 2002).…”