Neuropeptide B and W: neurotransmitters in an emerging G-protein-coupled receptor system

Abstract

Deorphanised G-protein-coupled receptors represent new and expanding targets for drug development. Neuropeptide B (NPB) and W (NPW) have recently been identified as the cognate endogenous ligands for the orphan receptor GPR7, now designated as NPBW(1). NPB and NPW also bound to a second related orphan receptor, GPR8, now designated as NPBW(2) that is present in humans but not rats or mice. In humans, high levels of NPW mRNA have been visualised in the substantia nigra, whereas moderate expression levels have been detected in the amygdala and hippocampus. In peripheral tissues, expression of NPW mRNA has been confirmed in the progenital system, comprising the kidney, testis, uterus, ovary and placenta, and also in stomach homogenates. Immunocytochemical, molecular biological and autoradiography techniques have revealed a discrete CNS distribution for NPBW(1) in human, mouse and rat. Highest expression of NPBW(1) mRNA and protein was identified in the amygdala and hypothalamic nuclei known to regulate feeding behaviour. [(125)I]-NPW bound with a single high affinity to rat amygdala, K(D)=0.44 nM and 150 fmol mg(-1) protein. Physiological studies demonstrate that intracerebroventricular infusion of NPBW(1) ligands modulates feeding behaviour, regulates the release of corticosterone, prolactin and growth hormone while also manipulating pain pathway. Mouse knockout models of the gene encoding either NPB or NPBW(1) have a gender-specific phenotype, with moderate obesity evident in males but not females. Further investigation is required to elucidate the precise physiological role of NPB and NPW as neurotransmitters.

Figure 1

Localisation of NPBW₁ in coronal sections of rat brain using [¹²⁵I]-NPW receptor autoradiography. [¹²⁵I]-NPW binding was detected to the (a) DVC, dorsal vagal complex, (b) PAG, periaqueductal grey, (c) SuG, superficial grey layer of superior colliculus, (d) MeA, medial amygdaloid nuclei, (e) SFO, subfornical organ, BST, bed nucleus of the stria terminalis, MPA, medial preoptic area and the SCh of rat brain (n=4). Specific binding was not detected in the presence of unlabelled NPW (f). Scale bar=1 cm. Reproduced with permission from Brain Research (Singh et al., 2004).

Figure 2

Bovine, human, mouse, porcine and rat amino-acid sequences of NPB and NPW. Sequence similarities between NPB and NPW orthologues are shown in black. Further identical amino acids within the NPB or NPW orthologues are shown in grey.

Figure 3

Mechanism of corticosterone secretion induced by NPB/NPW. NPB/NPW released from afferents terminating at the PVN cause depolarisation, resulting in the release of CRF from the PVN into the hypothalamopituitary portal vessels. Once arriving at the anterior pituitary, CRF acts on the cells to induce secretion of ACTH, which is then released in the venous circulation. On arriving to the adrenal cortex, ACTH acts to promote the secretion of corticosterone, which then has its effects on glucose production, protein and triacylglycerol catabolism as well as stimulating appetite (Dallman et al., 2004; la Fleur et al., 2004).