Disease relevance of OPRL1

• A 60-min activation of mu-or opioid receptor-like 1 (ORL1) opioid receptors natively expressed in BE(2)-C human neuroblastoma cells desensitized both mu- and ORL1 receptor-mediated inhibition of cAMP accumulation [1].
• In most tissues and cells the opioid receptor-like (ORL1) receptor regulates effectors primarily through the pertussis toxin (PTX)-sensitive guanine nucleotide-binding regulatory proteins (G proteins) Gi/Go [2].
• Functional expression, activation and desensitization of opioid receptor-like receptor ORL1 in neuroblastoma x glioma NG108-15 hybrid cells [3].
• The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway [4].
• In air-free aqueous solutions, ROOH photosensitization always gave rise to a mixture of hydroxyl and peroxyl radical (*OOR) adducts in varying molar ratios [5].

Psychiatry related information on OPRL1

• The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction [6].
• No association between polymorphisms in the lectin-like oxidised low density lipoprotein receptor (ORL1) gene on chromosome 12 and Alzheimer's disease in a UK cohort [7].
• Lack of polymorphism in genes encoding mGluR 7, mGluR 8, GABA(A) receptor alfa-6 subunit and nociceptin/orphanin FQ receptor and panic disorder [8].

High impact information on OPRL1

• ORL1 transcripts are particularly abundant in the central nervous system [9].
• Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities [10].
• Human PMN express mRNA for Noci-R, its nucleotide sequence determined, and specific binding with [(125)I]-labeled nociceptin gave an apparent K(d) approximately 1.5 nM for this PMN opioid receptor [11].
• Here, we report that Noci-R is present and functional on peripheral blood polymorphonuclear leukocytes (PMN) [11].
• UV irradiation at 365 nm of the complex formed by the ORL1 receptor and radioiodinated [Bpa(10),Tyr(14)]noc results in the irreversible labeling of a glycoprotein of approximately 65 kDa, determined by SDS-polyacrylamide gel electrophoresis [12].

Chemical compound and disease context of OPRL1

• However, in SH-SY5Y neuroblastoma cells, DAMGO failed to desensitize ORL1 or alter membrane PKC-alpha or GRK levels [1].

Biological context of OPRL1

• The transcription and alternative splicing of human ORL1 are controlled by two alternate promoters, located approximately 10 kb apart [13].
• Two different repeat sequence polymorphisms are found in the ORL1 promoter regions [13].
• A potential ATG codon upstream of the initiation codon of ORL1 starts a new open-reading frame encoding a theoretical polypeptide of 205 amino acid residues [13].
• The first exons of ORL1 and GAIP are separated by only 83 bp [13].
• To better understand opioid receptor-like 1 (ORL1) internalization, we fused the C terminus of ORL1, the nociceptin (noc) receptor, to the N terminus of a green fluorescent protein and used the fusion protein to characterize receptor endocytosis in live human embryonic kidney cells [14].

Anatomical context of OPRL1

• Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells [15].
• Coincubation of the recombinant cells with noc and tetramethylrhodamine-transferrin showed that ORL1 was mainly internalized through the endosome compartment [14].
• The molecular mechanism(s) underlying cross-tolerance between mu and opioid receptor-like 1 (ORL1) receptor agonists were investigated using two human neuroblastoma cell lines endogenously expressing these receptors and G protein-coupled receptor kinases (GRKs) [16].
• As predicted by the type 2 adenylyl cyclase assays, activation of the ORL1 receptor resulted in the formation of inositol phosphates in COS-7 cells transiently cotransfected with Galpha14 [2].
• Nociceptin receptor mRNA is expressed in human trigeminal ganglia but not in basilar arteries [17].

Associations of OPRL1 with chemical compounds

• Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics [6].
• Alanine mutation, in the human ORL1 receptor, of transmembrane amino acid residues that are conserved in opioid receptors, Asp(130) and Tyr(131) in transmembrane segment (TM) III, Phe(220) and Phe(224) in TM V, and Trp(276) in TM VI, yields mutant receptors with reduced affinity, and proportionally decreased reactivity, toward nociceptin [18].
• Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain [18].
• Antisense, but not sense, DNA selectively targeting GRK2 or GRK3 blocks DAMGO-mediated mu- and ORL1 desensitization, respectively [1].
• To allow the rapid identification of agonists and antagonists, a reporter gene assay has been established in which the ORL1 receptor is functionally linked to the cyclic AMP-dependent expression of luciferase [19].

Physical interactions of OPRL1

• These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes [20].
• In oocytes from Xenopus laevis, NOX 2149 showed an antagonistic effect to the N/OFQ-ORL 1 receptor system that was functionally coupled with G-protein-regulated inwardly rectifying K(+) channels [21].

Regulatory relationships of OPRL1

• Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions [22].
• Prolonged (24 h) activation of the mu receptor desensitized both mu and ORL1 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation and upregulated GRK2 levels in SH-SY5Y and BE(2)-C cells [16].
• As anticipated, nociceptin receptor activation inhibits the formation of cAMP formation via a pertussis toxin-sensitive G-protein [23].

Other interactions of OPRL1

• A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP [13].
• Reduction of GRK2 and GRK3 levels by antisense, but not sense DNA treatment blocks ORL1 and mu receptor desensitization [22].
• Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid receptor-like receptor or nociceptin receptor (NOP) [24].
• Activation of mu or ORL1 receptors in these cells in turn activates extracellular signal-regulated protein kinases (ERKs), ERK1 and ERK2 [25].
• Coupling to both Gz and G16 was expected because close relatives of the ORL1 receptor, the opioid receptors, are known to couple productively to these G proteins [2].

Analytical, diagnostic and therapeutic context of OPRL1

• A site-directed mutagenesis approach has been used to gain insight into the molecular events whereby the heptadecapeptide nociceptin binds and activates the opioid receptor-like 1 (ORL1) receptor, a G protein-coupled receptor [18].
• In addition, we studied the nociceptin receptor at mRNA levels by RT-PCR and the vasomotor response to nociceptin in human cerebral vessels using a sensitive in vitro method [17].
• Using in situ hybridization techniques, the present study was undertaken to determine the normal pattern of expression of ORL1 mRNA in the human and rat brain at various developmental stages [26].
• Ovariectomies were performed on female Sprague-Dawley rats, and their plasma luteinizing hormone (LH) levels were measured after icv injection of OFQ with or without [Nphe1]NC(1-13)NH2, a competitive antagonist of opioid receptor-like1 receptor (ORL1 receptor) [27].
• The tissue distribution of the nORL receptor, as determined by reverse transcriptase PCR, was also found to differ from reports on the mammalian ORL1 receptor, with mRNA detected in brain, spinal cord, and lung, but not detected in a number of other peripheral tissues reported to express the receptor in mammals [28].

References