NEUROPEPTIDE W-30 (HUMAN)

Structure

NPW cDNA encodes two forms of the peptide ligand with lengths of 23 and 30 aa residues as mature peptides, NPW23 and NPW30. These neuropeptides are derived from a common precursor protein, proNPW, by the proteolytic processing of two pairs of arginine residues at positions 24 and 25, and 31 and 32. Synthetic NPW23 activates and binds to two NPB/W receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), at similar effective doses. NPW precursor proteins are found in terrestrial vertebrate species, including mammals, birds, reptiles, and amphibians.  Human NPW23: Mr 2584.03; pI 10.28, Human NPW 30: Mr 3543.1; pI 11.0. Soluble in water. For best results, rehydrate just before use. After rehydration, keep solution at + 4°C for up to 5 days or freeze at -20°C for up to 3 months.

Gene, mRNA, and precursor

The gene encoding NPW maps to human chromosome 16p13.3. The gene encompasses 10.08 kb and is divided into two exons. Human NPW mRNA is 751 bp long. Among the porcine, rat, and human, the aa identities of NPW23 and NPW30 are 91.3% and 90.0%, respectively.  Based on RT-PCR analysis, NPW mRNA is highly expressed in the substantia nigra and spinal cord, and moderately expressed in the hippocampus, amygdala, hypothalamus corpus callosum, cerebellum, and dorsal root ganglia in the human central nervous system (CNS). In the peripheral tissues of rodents, Npw mRNA is expressed in the trachea, adrenocortical cells, gastric antral G cells, thyroid and parathyroid glands, pancreatic islets, ovary, and testis.

Receptors

Human NPBWR1 and NPBW2 genes are located on chromosome 10q11.2–121.1 and 20q13.3, respectively. Both receptors have 328 (36.1 kDa) and 333 (36.8 kDa) aa residues, respectively, and share 64% sequence homology with each other.8 NPBWR1 orthologs are highly conserved among other mammalian species. In contrast, the gene encoding NPBWR2 has not found in rodent genomes, suggesting that these two receptors were produced by relatively phylogenetically recent gene duplication. NPBWR1 and NPBWR2 couple to the Gi-class of G-proteins but not the Gq-class, suggesting that NPW has inhibitory properties on neurons via the activation of GIRK (Kir3) channels. NPW stimulated the PKA, PKC, p38 MAPK, and ERK1/2 activities in a dose- and time-dependent manner via NPBWR1 in the ATDC5 cells.

Biological functions

In mammals, NPW regulates many physiological processes such as food intake, energy homeostasis, obesity, neuroendocrine activity, and social behavior via its action on the CNS. In addition to the CNS, NPW and its receptors are expressed in the peripheral tissues of rodents or humans, such as the pancreas, stomach, adrenal cortex, anterior pituitary, and adipocytes. NPW may be involved in the control of adrenal corticosterone secretion, pancreatic insulin secretion, and lipolysis. Phenotype of gene-modified animals NPW knockout mice behave abnormally in response to life-threatening events (i.e., pain stimuli or a potential predator) when the environment is novel and/or distracting. NPBWR1 knockout male mice show late-onset obesity and hyperphagia, suggesting that the endogenous NPB/NPW-NPBWR1 pathway negatively regulates feeding behavior and positively regulates energy expenditure. However, these phenotypic characteristics are not observed in females.

Clinical implications

Direct linking between human diseases and the NPWNPBWR system has not been clarified yet. However, NPBWR1 modulates feeding, metabolism, and obesity in male mice. In humans, abdominal obesity is more prevalent in males, and is an independent risk factor for coronary heart disease. As activating or disrupting the NPW-NPBWR1 system does not have pronounced effects on growth and mortality in mice, NPBR1 and its ligand may be helpful for the discovery of therapeutic drugs and for designing therapies that overcome obesity and other lifestyle-related disorders .

Synthesis and release

In the rat stomach, NPW is secreted in response to the acute ingestion of a standard laboratory diet. Plasma NPW concentrations in fasting rats are low, and increase in response to feeding. Npw mRNA expression and the number of NPW-positive cells in the mouse antrum increase in diets including protein or glucose.

Description

The 23- or 30-aa neuropeptide identified as a ligand for two orphan G-protein-coupled receptors (GPR7 and GPR8), neuropeptide W (NPW) is involved in the regulation of feeding behavior and energy homeostasis via the neuronal circuits of the hypothalamus. O’Dowd et al. reported the existence of human genes encoding two structurally related orphan G protein-coupled receptors, NPBWR1 (GPR7) or NPBWR2 (GPR8).1 However, the endogenous ligand for these orphan receptors remained unknown until 2002. Shimomura et al. identified the mature peptide sequences of neuropeptide B (NPB) and neuropeptide W (NPW) from the porcine hypothalamus by reverse pharmacology.