A human gene encoding morphine modulating peptides related to NPFF and FMRFamide

Abstract

FMRFaraide-related peptides have been isolated from both invertebrates and vertebrates and exhibit a wide range of biological effects in rats. We show here that in humans 2 FMRFamide-related peptides are encoded by a single gene expressed as a spliced mRNA. The larger predicted peptide (AGEGLNSQFWSLAAPQRFamide) differs from the peptide isolated from bovines (AGEGLSSPFWSLAAPQRFamide) by the substitutions of 2 amino acids. The shorter predicted peptide (NPSF, SQAFLFQPQRFamide) is 3 amino acids longer than the bovine 8 amino-acid NPFF (FLFQPQRFamide) or the human NPFF peptide isolated from serum [5], suggesting that the encoded protein is subject to cleavage by a tripeptidyl peptidase or by a novel processing mechanism. On rat spinal cord, the larger peptide is indistinguishable in activity from the equivalent bovine peptide whereas the smaller extended peptide is inactive.© 1997 Federation of European Biochemical Societies.Key words: NPFF; NPAF; FMRFamide; cDNA; Nociception; Human In bovine brain, 3 different forms of immunoreactive material were detected by HPLC separation and the use of an antibody raised against the molluscan peptide FMRF-NH 2 . Two of these correspond to NPFF and NPAF ; the structure of the third is unknown [12]. Similarly, in the rat hypothalamus, NPFFs have been shown to exist by HPLC and immunoreactivity but the predominant form of peptide is not NPFF [13].The isolation of the human gene described here now allows a definitive description of the human FMRFamide peptides. We show that there is an additional 3 amino acids on the human NPFF precursor that must be cleaved to produced biologically active NPFF. If these amino acids are present on the precursor of the bovine and rat NPFF then this could account for the alternate form detected by HPLC. We also demonstrate that human NPAF is capable of modulating neural activity in the rat spinal cord in a manner indistinguishable from that of bovine NPAF while human N-terminally extended NPFF has no activity.

Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity

“…Up to now, three cDNAs encoding RFRPs have been identified in human (4,5,11,14). In the present study, we have characterized a fourth cDNA encoding a neuropeptide designated 26RFa that exhibits weak structural similarity with the other RFRPs described so far.…”

“…Notably, in human, only three genes encoding RFRPs precursors have been characterized to date. One of these genes encodes the precursor for two RFRPs, i.e., neuropeptide FF (NPFF) and neuropeptide AF (4,5). These two neuropeptides modulate the action of morphine (6) and are thus thought to be involved in the transmission of pain stimuli.…”

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

“…by norepinephrine) of energy expenditure in situations that could increase NPAF levels. It has been reported that neuropeptide FF, and possibly NPAF, which is encoded by the same gene precursor (12,13), is secreted in the plasma in a pulsatile manner suggesting that the peptides could act as hormones (15). Under conditions of chronic increase in plasma NPAF, it can be anticipated that modifications of adipocyte catecholamine responsiveness could occur.…”

“…The gene encoding the precursor for these peptides has been recently described in human, rat, mouse, and bovine species (12,13); the two peptides are encoded as a single copy by the same precursor. In the rat, expression of the NPAF and NPFF precursor is limited to discrete regions of the central nervous system including the hypothalamus, medulla, and dorsal horn of the spinal chord (13).…”

Identification of proNeuropeptide FFA peptides processed in neuronal and non‐neuronal cells and in nervous tissue

“…Two precursors, proNPFF A and proNPFF B encoding peptides possessing the PQRFamide sequence, have been cloned in mammals [3,4]. The proNPFF A precursor at basic proteolytic sites should generate two PQRFamide containing peptides [3] and the proNPFF B , also called RFamide-related peptides precursor [5], contains a PQRFa sequence and an LPLRFa-containing peptide.…”