NPFF Neuropeptide FF (FLFQPQRFa) is a mammalian amidated neuropeptide originally isolated from bovine brain and characterized as a pain-modulating peptide, with anti-opioid activity on morphine-induced analgesia.
In humans, Neuropeptide FF peptides are encoded by the NPFF gene. Two genes encoding two different receptors (NPFF1 and NPFF2) and two precursors (NPFFA and NPFFB) have been cloned in several mammalian species. [5] [6]
Neuropeptide FF (NPFF) and RFamide related peptides issued from two precursors interact with good affinity with two subtypes of G protein-coupled receptors, namely NPFF1 and NPFF2 subtypes and are involved in several physiological functions such as cardiovascular regulation, hormonal control, macrophage activation, body temperature homeostasis and pain modulation. [6]
Processing of the NPFFA precursor at basic proteolytic sites should generate a NPFF-containing peptide with three additional N-terminal amino acids different between species, and a NPSF (SLAAPQRFa)-containing peptide, the length of which depends on the species. NPFFB, identified as a precursor for RFamide-related peptides (RFRPs, also called GnIH for gonadotropin inhibitory hormone), contains a LPLRFa-containing peptide and a peptide sharing with NPFF the same C-terminal PQRFamide motif, such as NPVF (VPNLPQRFa) in human.
NPFF and opioid systems have been shown to interact at several levels, from animal behavior to receptor molecules. Nociception is the physiological function in which this interaction has been the most extensively studied but reward, locomotion, feeding and intestinal motility are also affected. Endogenous opioids are necessary for the analgesic properties of spinally injected NPFF while endogenous NPFF peptides are involved in the process of analgesic tolerance/hyperalgesia induced by chronic opioid treatment.
NPFF also controls the number and metabolic effects of adipose tissue macrophages, and NPFF is necessary for adipose tissue health. [7]
Precortistatin is a protein that in humans is encoded by the CORT gene. The 105 amino acid residue human precortistatin in turn is cleaved into cortistatin-17 and cortistatin-29. Cortistatin-17 is the only active peptide derived from the precursor. Cortistatin is a neuropeptide that is expressed in inhibitory neurons of the cerebral cortex, and which has a strong structural similarity to somatostatin. Unlike somatostatin, when infused into the brain, it enhances slow-wave sleep. It binds to sites in the cortex, hippocampus and the amygdala.
Beta-Endorphin or β-Endorphin, is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.
Gastrin-releasing peptide, also known as GRP, is a neuropeptide, a regulatory molecule that has been implicated in a number of physiological and pathophysiological processes. Most notably, GRP stimulates the release of gastrin from the G cells of the stomach.
Opioid peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake.
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor, and initiates its function to act on numerous brain activities such as pain sensation and fear learning. It is derived from the prepronociceptin protein, as are a further 2 peptides, nocistatin & NocII, which inhibit the N/OFQ receptor function. Nociceptin itself acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers. The gene coding for prepronociceptin is located on Ch8p21 in humans. Nociceptin acts at the Nociceptin receptor formerly known as ORL1. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995.
Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids.
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
The neuropeptide FF receptors are members of the G-protein coupled receptor superfamily of integral membrane proteins which bind the pain modulatory neuropeptides AF and FF. The Neuropeptide FF receptor family is a member of the G protein-coupled receptor superfamily containing two subtypes, NPFF1 and NPFF2, which exhibit a high affinity for Neuropeptide FF (NPFF) peptides. NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density, particularly in mammals in the superficial layers of the spinal cord where it is involved in nociception and modulation of opioid functions These receptors participate to the modulation of opioid receptor function in the brain and spinal cord, and can either reduce or increase opioid receptor function depending which tissue they are released in, reflecting a complex role for neuropeptide FF in pain responses.
Calcitonin receptor-like (CALCRL), also known as the calcitonin receptor-like receptor (CRLR), is a human protein; it is a receptor for calcitonin gene-related peptide.
Neuropeptides B/W receptor 1, also known as NPBW1 and GPR7, is a human protein encoded by the NPBWR1 gene. As implied by its name, it and related gene NPBW2 are transmembranes protein that bind Neuropeptide B (NPB) and Neuropeptide W (NPW), both proteins expressed strongly in parts of the brain that regulate stress and fear including the extended amygdala and stria terminalis. When originally discovered in 1995, these receptors had no known ligands and were called GPR7 and GPR8, but at least three groups in the early 2000s independently identified their endogenous ligands, triggering the name change in 2005.
Neuropeptides B/W receptor 2, also known as NPBW2, is a human protein encoded by the NPBWR2 gene.
Neuropeptide Y receptor type 1 is a protein that in humans is encoded by the NPY1R gene.
Neuropeptide Y receptor type 2 (Y2R) is a member of the neuropeptide Y receptor family of G-protein coupled receptors, that in humans is encoded by the NPY2R gene.
Neuropeptide FF receptor 2, also known as NPFF2 is a human protein encoded by the NPFFR2 gene.
Neuropeptide FF receptor 1, also known as NPFF1 is a human protein, encoded by the NPFFR1 gene.
Pyroglutamylated RFamide peptide receptor also known as orexigenic neuropeptide QRFP receptor or G-protein coupled receptor 103 (GPR103) is a protein that in humans is encoded by the QRFPR gene.
Pancreatic polypeptide receptor 1, also known as Neuropeptide Y receptor type 4, is a protein that in humans is encoded by the PPYR1 gene.
RF(Arg-Phe)amide family 26 amino acid peptide, also known as P518, is a human protein.
RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).
Neuropeptide VF precursor, also known as pro-FMRFamide-related neuropeptide VF or RFamide-related peptide precursor, is a propeptide that in mammals is encoded by the NPVF (or RPFP) gene. The NPVF gene, and thus the propeptide, are expressed in neurons in the mediobasal hypothalamus. The propeptide is cleaved to form three other peptides, which are:
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