Structure and Regional Distribution of Nociceptin/Orphanin FQ Precursor

Houtani, Takeshi; Nishi, Miyuki; Takeshima, Hiroshi; Nukada, Toshihide; Sugimoto, Tetsuo

doi:10.1006/bbrc.1996.0300

Cited by 140 publications

(65 citation statements)

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“…The 194-residue sturgeon proorphanin is smaller than the 254-residue Cavia porcellus prodynorphin (33), which is the smallest classical opioid precursor yet characterized, but larger than all previously reported orphanin precursors, which range from 175 to 186 residues (34,35). Parsimonious sequence alignments reveal that among mammalian proorphanin sequences, size variants are the result of redundancy of a hexapeptide (DAEP(E/V)A in rats and DA-EPGA in mice) beginning at residue 109 in rodent sequences (Fig.…”

Section: Discussionmentioning

confidence: 73%

Sturgeon Orphanin, a Molecular “Fossil” That Bridges the Gap between the Opioids and Orphanin FQ/Nociceptin

Danielson

Hoversten

Fitzpatrick³

et al. 2001

Journal of Biological Chemistry

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The elucidation of the cDNA sequence for sturgeon proorphanin provides a unique window for interpreting the evolutionary history of the opioid/orphanin gene family. The molecular "fossil" status of this precursor can be seen in several ancestral sequence characteristics that point to its origin as a duplication of either a prodynorphin-or proenkephalin-like gene. The sturgeon proorphanin cDNA encodes a precursor protein of 194 residues, and the orphanin heptadecapeptide itself binds not only the opioid receptor-like 1 (ORL1) receptor but also the classical (, , and ␦) opioid receptors with near equal affinity. Allowing for this broad receptor specificity are several amino acid substitutions at key positions in the heptadecapeptide sequence, relative to its mammalian orthologs, that have been linked by amino acid scans and site-directed mutagenic studies to the exclusion of mammalian orphanin FQ/nociceptin from classic opioid ligands (i.e. F1Y and L14W). The unique receptor binding profile of sturgeon orphanin not only provides insight into the evolutionary history of the opioid and opioid-related peptides but also provides an ideal context in which to investigate the underlying mechanisms by which novel and often divergent physiological functions arise in receptor-ligand systems.The expansion and functional diversification of multigene families have been a recurring theme in the evolutionary success of complex eukaryotic organisms (1), and the opioid neuropeptides clearly illustrate this phenomenon (2). The classic opioid gene family comprises three neuropeptide precursors encoded on the following genes: proopiomelanocortin (end products: ␤-endorphin, melanocyte-stimulating hormone-associated peptides), proenkephalin (end products: Met-enkephalin, Leuenkephalin), and prodynorphin (end products: dynorphins and ␣-neoendorphin). Based on the organization of these genes it appears that they were derived from a common ancestral gene (3). This hypothesis is supported by the shared neuroinhibitory action of the opioid end products and the selective binding profiles of the opioid peptides to a family of G protein-coupled receptors (, , and ␦ opiate receptors) (4, 5).What has been difficult to resolve is the pattern of evolutionary events that has given rise to the opioid gene family. This is an issue that has been further complicated by the discovery, reported simultaneously by Meunier et al. (6) and Reinscheid et al. (7), of the 17-amino acid orphanin FQ/N, 1 the endogenous ligand for the opioid receptor-like 1 (ORL1) receptor, the "orphan" opiate receptor gene. The organization of the orphanin FQ/N precursor (proorphanin or pronociceptin) indicates that this gene is evolutionarily related to the opioid-coding precursor genes. Mammalian proorphanin has the same basic intronexon structure, conserved N-terminal cysteines, and a modified opioid-like core sequence (FGGF instead of YGGF) that are all defining features of classic opioid precursors. Similarities are also seen at the cellular level where both typical opioids ...

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Section: Discussionmentioning

confidence: 73%

Sturgeon Orphanin, a Molecular “Fossil” That Bridges the Gap between the Opioids and Orphanin FQ/Nociceptin

Danielson

Hoversten

Fitzpatrick³

et al. 2001

Journal of Biological Chemistry

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“…As expected, nociceptin/orphanin FQ exhibits a nanomolar affinity for the ORLi receptor and a low affinity for the μ, δ, κ opioid receptors despite the presence in N-terminal position of the FGGF sequence instead of YGGF in endogenous opioid receptor ligands. Although the functional role of nociceptin/orphanin FQ remains unknown, the wide distribution of ORLi mRNA and nociceptin/orphanin FQ precursor in the central nervous system of rodents, particularly in the limbic system and in several areas known to be involved in the control of nociceptive stimuli, including the spinal cord dorsal horn, have suggested that this peptide could be involved in pain perception [2][3][4][5][11][12][13]. The peptide has been reported to heighten sensitivity to pain following i.c.v.…”

Section: Introductionmentioning

confidence: 99%

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Noble

Roques

1997

FEBS Letters

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The behavioral effects induced by central administration in mice of the endogenous ORLj (opioid receptor-like]) ligand, nociceptin/orphanin FQ, were investigated in the absence or presence of inhibitors of aminopeptidase N (bestatin) and endopeptidase 24.15 (Z-(L!D) PheT(P0 2 CH 2 )(L,D)Ala-Arg-Phe) recently shown to be involved in the metabolism of the heptadecapeptide in vitro. A severe reduction in motor activity induced by nociceptin/orphanin FQ was measured in two tests (spontaneous motor activity and open field). This pharmacological effect was shown to be potentiated by the association of bestatin and Z-(LiD )PheT(P0 2 CH2)(L,D)Ala-Arg-Phe, confirming in vivo the involvement of these peptidases in nociceptin/ orphanin FQ inactivation. In our conditions, these inhibitors were devoid of intrinsic effects, suggesting a low tonic regulation by the heptadecapeptide of the measured behaviour.

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“…uleus, periacqueductal gray, amygdala, and hypothalamic and septal regions (1,29,30,42,44,49). These locations suggest that the nociceptinergic system may play a role in modulation of physiological activities, such as regulation of pain and autonomic outflow, much like the classical endogenous opioid system.…”

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confidence: 99%

Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats

Crisostomo¹,

Li²,

Tjen‐A‐Looi³

et al. 2005

Journal of Applied Physiology

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. Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats. J Appl Physiol 98: 2056 -2063, 2005. First published January 13, 2005; doi:10.1152/japplphysiol.01282.2004 at Neiguan-Jianshi acupoints through an opioid mechanism inhibits the cardiovascular pressor response induced by mechanical stimulation of the stomach. Because nociceptin also may regulate cardiovascular activity through its action in the brain stem, we hypothesized that this neuromodulator serves a role in the EA-related inhibitory effect. Blood pressure in ventilated male Sprague-Dawley rats (400 -600 g) anesthetized by ketamine and ␣-chloralose was measured during balloon inflation of the stomach. Gastric distension with 6 -8 ml of air induced consistent pressor reflexes of 26 Ϯ 1 mmHg that could be repeated every 10 min for 100 min. When nociceptin (10 nM) was microinjected into the rostral ventrolateral medulla (rVLM), the pressor response induced by gastric distension was inhibited by 68 Ϯ 6%. Thirty minutes of EA also decreased the reflex response by 75 Ϯ 11%; microinjection of saline into the rVLM did not alter the inhibitory effect of EA. In contrast, microinjection of a nociceptin receptor antagonist into the rVLM promptly reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not influence the EA-like inhibitory effect of nociceptin on the distension-induced pressor reflex (22 Ϯ 1 to 8 Ϯ 2 mmHg). Furthermore, a -opioid receptor agonist microinjected into the rVLM after microinjection of a nociceptin receptor antagonist during EA promptly reversed the nociceptin receptor antagonist-related inhibition of the EA effect. Thus, in addition to the classical opioid system, nociceptin, through opioid receptor-like-1 receptor stimulation in the rVLM, participates in the modulatory influence of EA on reflexinduced increases in blood pressure. opioids; gastric distension; somatic afferent RECENTLY, A NOVEL OPIATE-LIKE heptadecapeptide was identified in rat brain extracts (41,46). The peptide, called nociceptin (41) or Orphanin FQ (46), has a high amino acid sequence homology to classical endogenous opioid peptides (i.e., endorphins, enkephalins, endomorphins, and dynorphins) and especially to dynorphin A. Furthermore, amino acid sequencing of the receptor believed to be specific for nociceptin, or opioid receptor-like-1 (ORL-1), was found to be 47-50% identical to that of the coding sequences of -, ␦-, and -opioid receptors (10,

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Structure and Regional Distribution of Nociceptin/Orphanin FQ Precursor

Cited by 140 publications

References 0 publications

Sturgeon Orphanin, a Molecular “Fossil” That Bridges the Gap between the Opioids and Orphanin FQ/Nociceptin

Sturgeon Orphanin, a Molecular “Fossil” That Bridges the Gap between the Opioids and Orphanin FQ/Nociceptin

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats

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