Neuropeptide FF receptor, type 2 (IPR005397)

Short name: NPFF_rcpt_2

Overlapping homologous superfamilies


Family relationships


Neuropeptide FF receptors [PMID: 10837915] belong to a family of neuropeptides containing an RF-amide motif at their C terminus which have a high affinity for the pain modulatory peptide neuropeptide NPFF (NPFF) [PMID: 10851242]. Neuropeptide FF (NPFF) receptors have two subtypes, neuropeptide FF receptor type 1 (NPFF1) and neuropeptide FF receptor type 2 (NPFF2), they are members of rhodopsin G protein-coupled receptor family. The neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation [PMID: 8804117, PMID: 9593588, PMID: 10612711, PMID: 20803521].

Comparing the distribution of NPFF1 and NPFF2 receptors in different species reveals important species differences [PMID: 14696013]. The NPFF1 receptor is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus, is thought to participate in neuroendocrine functions. Whereas as the NPFF2 receptor is present in high density, particularly in mammals in the superficial layers of the spinal cord [PMID: 16443306] where it is involved in nociception and modulation of opioid functions [PMID: 17224450], consistent with a potential role of NPFF in the modulation of sensory inputs, like pain responses [PMID: 17854890, PMID: 18804517, PMID: 18823989].

This entry represents NPFF2, which is expressed at high levels in the thymus and placenta, with moderate levels in the pituitary, spleen, testis and brain. Low levels were detected in the spinal cord, pancreas, small intestine, uterus, stomach, lung, heart and skeletal muscle. No expression was detected in liver or kidney [PMID: 11325803]. The NPFF2 receptor has been found to regulate adenylyl cyclase in some recombinant cell lines [PMID: 10851242, PMID: 10851242]. In acutely dissociated neurons, the NPFF2 receptors specifically counteract N-type Ca2+ channel inhibition by opioids [PMID: 10536200, PMID: 12932818]. In SH-SY5Y neuroblastoma cells stably expressing human NPFF receptors, NPFF agonists also reduce the inhibitory effect of mu-opioid and delta-opioid receptor activation on an N-type Ca2+ channel [PMID: 16488058, PMID: 15608144]. These regulations could be due in part to receptor heteromerisation since NPFF2 receptors have been shown to physically interact with mu-opiod receptors [PMID: 17224450]] and induce their trans-phosphorylations [PMID: 22375000].

GO terms

Biological Process

GO:0007186 G-protein coupled receptor signaling pathway
GO:0043408 regulation of MAPK cascade
GO:0045761 regulation of adenylate cyclase activity
GO:2000479 regulation of cAMP-dependent protein kinase activity

Molecular Function

GO:0008188 neuropeptide receptor activity
GO:0031628 opioid receptor binding

Cellular Component

GO:0016021 integral component of membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.