Identification and Characterization of Novel Mammalian Neuropeptide FF-like Peptides That Attenuate Morphine-induced Antinociception

Liu, Qingyun; Guan, Xiaofei; Martin, William J.; McDonald, Terrence; Clements, Michelle K.; Jiang, Qingping; Zeng, Zhizhen; Jacobson, Marlene A.; Williams, David L.; Yu, Hong; Bomford, Douglas; Figueroa, David J.; Mallee, John; Wang, Ruiping; Evans, Jilly F.; Gould, Robert J.; Austin, Christopher P.

doi:10.1074/jbc.m105308200

Cited by 245 publications

(318 citation statements)

References 39 publications

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“…1), similar to that reported for the human-or rat-cloned NPFF-R2 (14,16,34,35), and that both NPFF-R1 and NPFF-R2 mRNAs were expressed in 3T3-L1 adipocytes (Fig. 2).…”

Section: Discussionsupporting

confidence: 71%

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

Lefrère

Coppet

Camelin

et al. 2002

Journal of Biological Chemistry

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(2000) J. Biol. Chem. 275, 25965-25971) suggested these peptides, principally recognized for their pain modulating effects, may also impact on adipocyte metabolism, an aspect that has not been explored previously. Our aim was thus to obtain more insights into the actions of these peptides on adipocytes, an approach initially undertaken with a functional genomic assay. First we showed that 3T3-L1 adipocytes express both NPFF-R1 and NPFF-R2 transcripts, and that NPAF binds adipocyte membranes with a nanomolar affinity as assessed by surface plasmon resonance technology. Then, and following a 24-h treatment with NPFF or NPAF (1 M), we have measured using real-time quantitative reverse transcriptase-PCR the mRNA steady state levels of already well characterized genes involved in key pathways of adipose metabolism. Among the 45 genes tested, few were modulated by NPFF (ϳ10%) and a larger number by NPAF (ϳ27%). Interestingly, NPAF increased the mRNA levels of ␤2-and ␤3-adrenergic receptors (AR), and to a lesser extent those of ␤1-ARs. These variations in catecholamine receptor mRNAs correlated with a clear induction in the density of ␤2-and ␤3-AR proteins, and in the potency of ␤-AR subtype-selective agonists to stimulate adenylyl cyclase activity. Altogether, these data show that NPFF-R1 and NPFF-R2 are functionally present in adipocytes and suggest that besides their well described pain modulation effects, NPAF and to a lesser extent NPFF, may have a global impact on body energy storage and utilization.

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“…1), similar to that reported for the human-or rat-cloned NPFF-R2 (14,16,34,35), and that both NPFF-R1 and NPFF-R2 mRNAs were expressed in 3T3-L1 adipocytes (Fig. 2).…”

Section: Discussionsupporting

confidence: 71%

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

Lefrère

Coppet

Camelin

et al. 2002

Journal of Biological Chemistry

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“…NPSF has almost equal affinity for GPR74 and GPR147, whereas NPFF has at least 10 times higher affinity for the former receptor. 10,13,14 Our results suggest that the two receptors mediate different effects on lipolysis. NPFF has no effect on catecholamineinduced lipolysis using the natural ligand noradrenaline alone.…”

Section: Discussionmentioning

confidence: 62%

“…Detailed examinations of signal transduction can only be carried out in cell systems with stable manipulation of the expression of either or both of the receptors. [5][6][7][8][9]13,14 Unfortunately at present it is not possible to carry out such studies in human adipocytes kept in primary culture. We therefore used an indirect approach by comparing the effect of NPFF with that of NPSF and by using selective lipolysis agents acting on defined steps in signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…NPFF has higher affinity for binding to GPR74 than for GPR147, whereas NPSF has equal binding affinity for GPR74 and GPR147. 10,13,14 Our primary hypothesis was that these neuropeptides are regulators of human fat cell lipolysis, which is achieved by interacting with their target receptors. The second hypothesis was that the neuropeptide regulation of lipolysis is influenced by obesity.…”

Section: Introductionmentioning

confidence: 99%

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Effects of pain controlling neuropeptides on human fat cell lipolysis

et al. 2010

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Objective: Neuropeptides NPFF and NPSF are involved in pain control, acting through the G-protein coupled receptors (GPR)74 (high affinity for NPFF) and GPR147 (equal affinity for NPFF and NPSF). GPR74 also inhibits catecholamine-induced adipocyte lipolysis and regulates fat mass in humans. The aim of this study was to compare the effects of NPFF and NPSF on noradrenalineinduced lipolysis and to determine the expression of their receptors in human fat cells. Design: Adipose tissue was obtained during surgery. Adipocytes were prepared and kept in primary culture. Lipolysis, protein expression and gene expression were determined. Results: NPFF counteracted noradrenaline-induced lipolysis, which was more marked after 48 h than after 4 h exposure and was solely attributed to inhibition of b-adrenoceptor signalling. NPSF counteracted noradrenaline-induced lipolysis maximally after 4 h of exposure, which was attributed to a combination of inhibition of b-adrenoceptor signalling and decreased activation of the protein kinase-A hormone sensitive lipase complex by cyclic AMP. Both neuropeptides were effective in nanomolar concentrations. NPFF and NPSF had no effects on the expression of genes involved in catecholamine signal transduction. Both GPR74 and GPR147 were expressed at the protein level in fat cells from various adipose regions. GPR74 mRNA levels were higher in adipose tissue from obese as compared with non-obese subjects. High gene expression of either receptor correlated with low noradrenaline-induced lipolysis (Po0.05). Conclusions: Pain controlling neuropeptides NPFF and NPSF may be important for the regulation of lipolysis in man probably acting through GPR74 and GPR147. At low concentrations they inhibit catecholamine-induced lipolysis through rapid and longterm post-transcriptional effects at several steps in adrenoceptor signalling in fat cells.

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“…These have been identified primarily by bulk purification from neuroendocrine tissues (10 -12). Additionally, an examination of cleavage sites within the precursors for endogenous peptides showed that nonclassical processing is required to release the peptide from its precursor (13)(14)(15). Finally, mass spectrometric techniques to identify neuropeptides in the brains of mice lacking specific processing enzymes such as CPE have led to the identification of products of nonclassical cleavages (16).…”

mentioning

confidence: 99%

Characterization of Endothelin-converting Enzyme-2

Mzhavia

Pan

Fei

et al. 2003

Journal of Biological Chemistry

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Most neuroendocrine peptides are generated by proteolysis of the precursors at basic residue cleavage sites. Prohormone convertases belonging to the subtilisin family of serine proteases are primarily responsible for processing at these "classical sites." In addition to the classical cleavages, a subset of bioactive peptides is generated by processing at "nonclassical" sites. The proteases responsible for these cleavages have not been well explored. Members of several metalloprotease families have been proposed to be involved in nonclassical processing. Among them, endothelin-converting enzyme-2 (ECE-2) is a good candidate because it exhibits a neuroendocrine distribution and an acidic pH optimum. To examine the involvement of this protease in neuropeptide processing, we purified the recombinant enzyme and characterized its catalytic activity. Purified ECE-2 efficiently processes big endothelin-1 to endothelin-1 by cleavage between Trp 21 and Val 22 at acidic pH. To characterize the substrate specificity of ECE-2, we used mass spectrometry with a panel of 42 peptides as substrates to identify the products. Only 10 of these 42 peptides were processed by ECE-2. A comparison of residues around the cleavage site revealed that ECE-2 exhibits a unique cleavage site selectivity that is related to but distinct from that of ECE-1. ECE-2 tolerates a wide range of amino acids in the P1-position and prefers aliphatic/aromatic residues in the P1-position. However, only a small fraction of the aliphatic/aromatic amino acid-containing sites were cleaved, indicating that there are additional constraints beyond the P1-and P1-positions. The enzyme is able to generate a number of biologically active peptides from peptide intermediates, suggesting an important role for this enzyme in the biosynthesis of regulatory peptides. Also, ECE-2 processes proenkephalin-derived bovine adrenal medulla peptides, and this processing leads to peptide products known to have differential receptor selectivity. Finally, ECE-2 processes PEN-LEN, an endogenous inhibitor of prohormone convertase 1, into products that do not inhibit the enzyme. Taken together, these results are consistent with an important role for ECE-2 in the processing of regulatory peptides at nonclassical sites.

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Identification and Characterization of Novel Mammalian Neuropeptide FF-like Peptides That Attenuate Morphine-induced Antinociception

Cited by 245 publications

References 39 publications

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

Effects of pain controlling neuropeptides on human fat cell lipolysis

Characterization of Endothelin-converting Enzyme-2

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