General

Neuropeptide W (NPW) has been described as an endogenous ligand for the G-protein coupled receptors NPBW1 [10] and NPBW2 [10]. The NPW family in mammals consists of two mature peptides which are derived from a larger precursor and through proteolytic processing forms either the mature 23 amino acid residue peptide (NPW-23) or the mature C-terminus extended peptide of 30 amino acids (NPW-30). These peptides were first identified from bovine hypothalamus and therefore are classed as neuropeptides. The nomenclature of these neuropeptides is derived from the single amino acid code for tryptophan (W) which is the first and last amino acid of NPW-30. Comparison of the amino acid sequence of NPW has revealed that the peptide is well conserved with different species. The NPW family shares highest homology with the neuropeptide B (NPB) family of peptides which has also been described as an endogenous ligand for NPBW1 and NPBW2 [2]. This latter family, similar to NPW, is derived from a larger precursor and through proteolytic processing and cleavage at basic pairs of amino acids, forms a 23 amino acid (NPB-23) and C-terminus extended form of 29 amino acids (NPB-29). The amino acid sequence is well conserved throughout evolution but rodents lack the first basic pairs of amino acid and as a consequence can only form NPB-29. The nomenclature of NPB is derived from the unique post-translational bromination of the first tryptophan residue.

NPB/W receptor

The NPB / NPW receptors, NPBW1 and NPBW2, are G-protein coupled receptors, previously designated orphan receptor GPR7 and GPR8, respectively. These receptors share highest homology to each other (64% amino acid homology) but also share considerable homology to the known opioid and somatostatin receptors. NPBW1 and NPBW2 couples to Gi leading to the inhibition of the enzymatic activity of adenylyl cyclase, resulting in the reduction of intracellular cAMP synthesis. The distribution of NPBW1 has been determined by a range of techniques (radioligand binding [11], northern blot [8], RT-PCR [2] and in situ hybridization [5,8]) in different species (rat, mouse and human) to discrete regions of the central nervous system. Highest expression has been reported in the amygdala and hypothalamic nuclei of the brain while lower levels have been detected in the pituitary and adrenal gland. The distribution of NPBW2 is similar to NPBW1 in humans.

Physiology

The NPB / NPW family have been implicated in the regulation of feeding in rodents [1,6-7,9-10]. Mouse knock out models of the NPBW1 gene develop sexually dimorphic adult onset obesity specific to males [4]. Other physiological effects of these receptors include modulation of response to inflammatory pain [12,14-15] and regulation of hormone release from the pituitary gland (resulting in enhanced secretion of prolactin [1,9-10], corticosterone [9,13] and suppressed growth hormone release [9]).

Pharmacology

The NPB / NPW family of peptides are specific to NPBW1 in rat and mouse as these species lack the NPBW1 homologue, NPBW2 [5]. In humans, there are no selective agonists of NPBW1 or NPBW2. Currently there are also no antagonists of NPBW1 or NPBW2. Both forms of the NPB and NPW family have similar potencies for NPBW1 and NPBW2 [2-3,10]. The unique post-translational bromination of Trp1-NPB family of peptides does not significantly alter potency [3,12] and therefore, the physiologic importance of this modification remains unknown. However, the N-terminus amino acids of both the NPB and NPW family are critical for receptor binding and signal transduction [12]. NPW-23 has been radio-iodinated and saturable, specific and high affinity binding has been described to sections of rat amygdala [11].

1. Baker JR, Cardinal K, Bober C, Taylor MM, Samson WK. (2003) Neuropeptide W acts in brain to control prolactin, corticosterone, and growth hormone release. Endocrinology, 144 (7): 2816-21. [PMID:12810535]

2. Brezillon S, Lannoy V, Franssen JD, Le Poul E, Dupriez V, Lucchetti J, Detheux M, Parmentier M. (2003) Identification of natural ligands for the orphan G protein-coupled receptors GPR7 and GPR8. J Biol Chem, 278 (2): 776-83. [PMID:12401809]

3. Fujii R, Yoshida H, Fukusumi S, Habata Y, Hosoya M, Kawamata Y, Yano T, Hinuma S, Kitada C, Asami T et al.. (2002) Identification of a neuropeptide modified with bromine as an endogenous ligand for GPR7. J Biol Chem, 277 (37): 34010-6. [PMID:12118011]

4. Ishii M, Fei H, Friedman JM. (2003) Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. Proc Natl Acad Sci USA, 100 (18): 10540-5. [PMID:12925742]

5. Lee DK, Nguyen T, Porter CA, Cheng R, George SR, O'Dowd BF. (1999) Two related G protein-coupled receptors: the distribution of GPR7 in rat brain and the absence of GPR8 in rodents. Brain Res Mol Brain Res, 71 (1): 96-103. [PMID:10407191]

6. Levine AS, Winsky-Sommerer R, Huitron-Resendiz S, Grace MK, De Lecea L. (2005) Injection of neuropeptide W into paraventricular nucleus of hypothalamus increases food intake. Am J Physiol Regul Integr Comp Physiol, 288: R1727-R1732. [PMID:15886360]

7. Mondal MS, Yamaguchi H, Date Y, Shimbara T, Toshinai K, Shimomura Y, Mori M, Nakazato M. (2003) A role for neuropeptide W in the regulation of feeding behavior. Endocrinology, 144: 4729-4733. [PMID:12959997]

8. O'Dowd BF, Scheideler MA, Nguyen T, Cheng R, Rasmussen JS, Marchese A, Zastawny R, Heng HH, Tsui LC, Shi X et al.. (1995) The cloning and chromosomal mapping of two novel human opioid-somatostatin-like receptor genes, GPR7 and GPR8, expressed in discrete areas of the brain. Genomics, 28 (1): 84-91. [PMID:7590751]

9. Samson WK, Baker JR, Samson CK, Samson HW, Taylor MM. (2004) Central neuropeptide B administration activates stress hormone secretion and stimulates feeding in male rats. J Neuroendocrinol, 16: 842-849. [PMID:15500544]

10. Shimomura Y, Harada M, Goto M, Sugo T, Matsumoto Y, Abe M, Watanabe T, Asami T, Kitada C, Mori M et al.. (2002) Identification of neuropeptide W as the endogenous ligand for orphan G-protein-coupled receptors GPR7 and GPR8. J Biol Chem, 277 (39): 35826-32. [PMID:12130646]

11. Singh G, Maguire JJ, Kuc RE, Fidock M, Davenport AP. (2004) Identification and cellular localisation of NPW1 (GPR7) receptors for the novel neuropeptide W-23 by [125I]-NPW radioligand binding and immunocytochemistry. Brain Res, 1017 (1-2): 222-6. [PMID:15261118]

12. Tanaka H, Yoshida T, Miyamoto N, Motoike T, Kurosu H, Shibata K, Yamanaka A, Williams SC, Richardson JA, Tsujino N et al.. (2003) Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8. Proc Natl Acad Sci USA, 100 (10): 6251-6. [PMID:12719537]

13. Taylor MM, Yuill EA, Baker JR, Ferri CC, Ferguson AV, Samson WK. (2005) Actions of neuropeptide W in paraventricular hypothalamus: implications for the control of stress hormone secretion. Am J Physiol Regul Integr Comp Physiol, 288 (1): R270-5. [PMID:15345475]

14. Yamamoto T, Saito O, Shono K, Tanabe S. (2005) Anti-hyperalgesic effects of intrathecally administered neuropeptide W-23, and neuropeptide B, in tests of inflammatory pain in rats. Brain Res, 1045 (1-2): 97-106. [PMID:15910767]

15. Zaratin PF, Quattrini A, Previtali SC, Comi G, Hervieu G, Scheideler MA. (2005) Schwann cell overexpression of the GPR7 receptor in inflammatory and painful neuropathies. Mol Cell Neurosci, 28 (1): 55-63. [PMID:15607941]