General

Neuromedin U (NmU) was first isolated from porcine spinal cord in 1985 and named for its potent contractile activity on the rat uterus [79]. Two molecular forms were purified; the icosapentapeptide (NmU-25) and an octapeptide (NmU-8) identical to the C-terminal of NmU-25 [79]. Both forms are biologically active, stimulating contraction of rat uterus in vitro and causing potent vasoconstriction in rats and dogs [29,79,118]. NmU has since been fully sequenced in several species including rat [20,78], dog [96], rabbit [56], frog [22,63,109], chicken [19,97], guinea pig [89], human [5], Japanese quail [115] and goldfish [72-73]. Most of the NmU analogues that have been isolated are icosapentapeptides with the exception of rat NmU-23 [16], tree-frog NmU-23 [109], Chinese toad NmU-17 [63], goldfish NmU-21 and NmU-38 (also has NmU-25) [73] and nonapeptides (NmU-9) from chicken [97] (also has NmU-25), guinea pig [89] and goldfish [72]. In pig and dog, both NmU-25 and NmU-8 are found, the latter most likely being generated from the former through proteolysis at a dibasic cleavage site (Arg16-Arg17) [79,96]. A comparison of the amino acid sequences of NmU reveals that the peptide has been remarkably conserved throughout evolution [10]. This degree of conservation, particularly of the amidated carboxyl-terminus is indicative of the importance of this for biological activity [21,40,79,108].

In addition to the potent contractile effect of NmU on rat uterus, several studies have demonstrated the tissue and species specificity of NmU contractile effects [7,11,52,79-80,100,135]. With time it has become clear that NmU is involved in a plethora of patho-physiological actions including: the regulation of blood pressure and regional blood flow [15,29,79-80,103,118,127,135]; the control of food intake, temperature and locomotor activity [6,9,23,36-37,43,47-48,61-62,92,136,141]; antidepressant and anxiolytic effects [126,128]; regulation of the stress response and the hypothalamic-pituitary-adrenal axis [30,49,61,68-69,130]; gastric emptying, acid secretion and ion transport [17,82]; nociception [12,22,93,131,140-141]; bone formation and remodelling [32,111]; insulin secretion and glucose homeostasis [54-55,99]; circadian rhythm [1,33,91,93]; inflammation, immunological responses and production of antibodies involved in arthritis [41,51,86-88,105]; addictive-type behaviours associated with food, drugs and alcohol [50,58-59,66,75,116,132-133]; complications associated with obesity such as non-alcoholic steatohepatitis [129]; cancer [2,24,28,38-39,60,64-65,104,114,120,137-138], and resistance to alectinib in the treatment of non-small cell lung cancer [139]. Whether relevant amounts of NmU enter the circulation to deliver remote effects is unclear although evidence suggests that NmU does not function as a circulating hormone. Transport of NmU into the brain across the blood-brain barrier has, however, been reported, at least raising the possibility of other mechanisms of action [31]. Indeed the half-life of any circulating NmU is less than 5 min [99]. Interestingly, thrombin has recently been reported as a key enzyme involved in the degradation of NmU in serum, hydrolysing an arginine-asparagine bond in the C-terminus [124]. The instability of circulating NmU, including exogenous NmU and related peptides has driven the search for more stable analogues or alternative agonists that might provide therapeutic potential.

More recently, the neuropeptide neuromedin S (NmS) has been identified as an endogeneous ligand for the same receptors that are responsible for mediating the effects of NmU [84]. NmS has also been identified in a number of species including man, rat, mouse and toad [13,84]. Peptides found in these species are of similar length (33-36 amino acids) with the exception of a 17 amino acid version found alongside a 33 amino acid version in toad [13]. The C-terminal heptapeptide of NmS is identical to that of mammalian forms of NmU and these peptides bind to the same receptors with similar affinity. Indeed, this heptapeptide is crucial for biological activity with even single amino acid substitutions in NmU-8 reducing functional effects [26,40]. Furthermore, amidation of the C-terminal asparagine is crucial for activity [10]. Despite structural similarities, NmS is not a splice variant of NmU, with the genes being located on different chromosomes [84-85]. Unlike NmU, which shows higher expression in the gastrointestinal tract than brain [5,119], with the notable exception of testes and spleen [27,83-84], NmS is mainly expressed in the central nervous system (CNS), particularly in the suprachiasmatic nucleus (SCN) of the hypothalamus (hence NmS), the site of the master circadian pacemaker in mammals [84]. Indeed, intracerebroventricular administration of NmS induces phase shifts in circadian rhythm of locomotor activity [84]. In addition, central administration of NmS inhibits food intake more potently and for longer than NmU [44,81,92]. NmS has also been found to potentiate the stress response and activate the hypothalamic-pituitary-adrenal axis [53], inhibit gastric emptying [4], contract human saphenous vein and chicken rectum smooth muscle [80,84], increase plasma levels of oxytocin [107], increase luteinizing hormone secretion [134] and potentially play a more important role in thermoregulation than NmU [90].

Although the precise pathophysiological roles of NmU and NmS perhaps remain to be fully defined, a major role for NmU in the regulation of food intake and energy balance are further supported by the phenotypes of mice in which NmU has either been knocked-out or overexpressed. Knockout mice have increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure [36]. In contrast, overexpression of NmU results in mice that are hypophagic, lighter, with reduced somatic and liver fat and improved insulin sensitivity [62]. Interestingly, a number of polymorphic variants of NmU have also been associated with childhood and adult obesity [35].

Receptors

Two previously orphan Family A, GPCRs, FM-3 (GPR66, SNORF62) and FM-4 (TGR-1, SNORF72) were identified as specific and functional receptors for NmU and have subsequently been designated NMU1 and NMU2 respectively [3,113]. Well before the molecular nature of the receptors had been identified, binding sites for NmU had been characterized. Thus, studies demonstrated saturable, specific and reversible binding of ¹²⁵I labelled rat NmU to membranes prepared from rat uterus that was dependent on time, temperature and pH [94]. However, in 1998, FM-3, was cloned from human and murine cDNA libraries due to its homology with the growth hormone secretagogue receptor (ghrelin receptor; 33% homology) and the neurotensin receptor (29% homology) [125]. Cloning enabled a subsequent reverse pharmacological approach that lead to the identification of NmU as its natural ligand [25,43,61,102,119]. NmU binds to and activates human FM-3 (NMU1) with sub-nanomolar affinity and potency respectively. Extracts from rat tissue were also found to contain a natural ligand for FM-3, with the brain and small intestine being most active and allowing rat NmU-23 to be purified chromatographically [78]. Screening of potential ligands at FM-3 found that only the various forms of NmU peptides provided potent activation. Peptides that show some similarity to NmU including the neuromedins B, C, K, and N, as well as neurotensin, ghrelin, motilin, vasoactive intestinal polypeptide and pancreatic polypeptide were inactive [61,102,119]. A BLAST search of the GenBank^TM genomic database using the NMU1 cDNA sequence revealed a human genomic fragment encoding a GPCR that was approximately 50% homologous to NMU1, previously known as FM-4 but now designated NMU2 [43]. NMU2 has been cloned from human, rat and mouse [26,42-43,102,112,125]. Both NMU1 (FM-3) and NMU2 (FM-4) reportedly have significant abilities to distinguish between different forms of NmU, and have species and tissue selectivity in the biological actions of NmU [18,100,135].


Both receptors exhibit many characteristics of Family A GPCRs, having the predicted seven-transmembrane helices and an ERY motif in the place of the conserved E/DRY motif at the junction of the third transmembrane domain and beginning of the second intracellular loop. In Family A GPCRs this is considered to regulate ligand binding and G-protein coupling [106,117]. There are also two cysteine residues present in the extracellular domain of both receptors that may allow the formation of a disulfide bridge to maintain protein folding, ligand binding and a stable conformation [117]. Amino acid sequence similarity between NMU1 and NMU2 is mainly confined to the transmembrane domains. Both receptors have putative phosphorylation sites within their intracellular domains [10] and NMU2 is phosphorylated in a recombinant system following activation with either NmU or NmS [101]. More recently a truncated version of NMU2 has been identified in a human ovarian cDNA. Data suggest that this is expressed at the cell surface as a six transmembrane protein. Although not directly responsive to NMU ligands, this truncated construct reportedly forms heterodimers with either NMU1 or NMU2 to attenuate signalling by reducing ligand binding [64].

NMU1

The gene for human NMU1 is localised to chromosome 2q37.1 and encoded by two exons [112]. NMU1 has been identified as both a 403 amino acid protein [125] and as a longer version with a 23 amino acid extended N-terminus, suggesting translation initiation from an in-frame, upstream AUG [102]. It is difficult to predict if one or both forms are expressed but the shorter form seems to have a stronger Kozak sequence and is more similar to the mouse orthologue [10]. This would give human (h) NMU1 a molecular mass of 44979 Da.

The mRNA for hNMU1 is expressed in a wide variety of tissues. In particularly the small intestines (in goblet cells in the ileum), adipose tissue, duodenum and jejunum, however mRNA is present at relatively high levels in the pancreas, stomach, testis, adrenal cortex, heart, spleen, pancreas, lung, trachea, mammary gland, bone marrow, smooth muscle and endothelial cells of cardiovascular tissues and peripheral blood leucocytes (particularly T and NK cells) [30,41,43,52,80,102,119]. A similar distribution pattern exists in the rat with highest levels in duodenum, jejunum, ileum, lung, femur and spleen [25,30]. NMU1 mRNA expression is also found in approximately 25% of the small/medium diameter neurones within the dorsal root ganglia [140]. There is relatively low or negligible expression of NMU1 in human or rodent brain [26,43].

Mice with knockout of NMU1 appear normal with respect to fertility, nociception, anatomy, behaviour and metabolism [98,131]. However, although acute and chronic peripheral administration of NmU reduces food intake and body weight in lean and diet-induced obese mice, these effects were absent in NMU1 knockout mice (NMU1^-/-) [99]. Further, although NmU administration also increases plasma levels of glucagon-like peptide 1 and PYY, the anorectic action of NmU is independent of signaling by either of these peptides or indeed on leptin signaling. Although NMU2 mediates central anorectic actions of NmU (see below), these data clearly highlight a role for NMU1 in peripheral anorectic actions of the peptide, which are at least in part dependent on vagal innervation of the abdomen [99].

NMU2

The gene for human NMU2 has been localised to chromosome 5q33.1. The genomic structure of NMU2 differs significantly from that of NMU1, in that the predicted open reading frame is encoded on four rather than two exons [112]. Two forms of human NMU2 have also been reported that differ in their initiating methionine; a 415 amino acid form [102,112] and a 412 amino acid form [42-43] with evidence perhaps being a little stronger for the shorter form [10], which has a predicted molecular mass of 47450 Da. 

In humans, NMU2 mRNA is confined predominantly to specific regions within the brain, with the greatest expression observed in the substantia nigra, medulla oblongata, pontine reticular formation, spinal cord and thalamus [42-43,102,112]. Moderate to high levels are also present in the indusium griseum, septohippocampal nucleus, vascular organ of the lamina terminalis, hypothalamic paraventricular nucleus, CA1 region of the hippocampus, parafasicular thalamic nucleus, dorsal raphe nucleus and along the ventral wall of the third ventricle in the hypothalamus [43]. Peripherally, the highest level is found in testis [102,112]. More recently, NMU2 mRNA has been found at much higher levels than NMU1 mRNA in human pancreatic cancer cell-lines and a pancreatic ductal adenocarcinoma [60]. In rat CNS, the hypothalamus has the highest NMU2 mRNA level, mainly in the wall of the third ventricle with moderate levels in the paraventricular nucleus and CA1 region of the hippocampus [34,43]. The high expression of NMU2 in specific regions of rat brain is also supported by a binding study in which [¹²⁵I]-rNMU-23 showed high binding in the limbic system, including the hypothalamus, amygadala and hippocampus [70]. The medulla oblongata, spinal cord, hippocampus and striatum show moderate to low levels of rNMU2 mRNA [25,30,42]. In rat periphery, the highest level of rNMU2 mRNA expression is in the uterus and ovary [25,30,42]. In contrast to the high expression level of NMU2 mRNA in rat uterus, it is mostly absent in uterus of human and dog, highlighting species-dependent differences in distribution and function [102,112,135].

The distribution of NMU2, particularly its localization in hypothalamic regions that are associated with the regulation of food intake and energy balance, are entirely consistent with a role for this receptor in mediating the reductions in food intake and energy expenditure following central administration of NmU [43-44,81,92]. Furthermore, in NMU2 knockout mice, central administration of NmU or NmS no longer has the effects seen in their wild-type counterparts such as the suppression of food intake, enhanced grooming and potentiated pain responses [98,141]. Based on such data, it might be expected that knockout of NMU2 would result in a hyperphagic, obese mouse. However, this appears not to be the case and the data present a rather confused picture. Thus, although NMU2 knockout mice exhibit reduced pain sensitivity, highlighting a critical role in the central processing of pain [131,141], they appear normal with respect to food consumption, body weight, fat composition and other aspects such as anxiety and stress [23,131,141]. Indeed NMU2^-/- mice have been reported as showing reduced food intake and reduced weight gain on either a regular or a high-fat diet, the latter indicating a resistance to diet-induced obesity [98]. In contrast, another study reported that female but not male NMU2^-/- mice had increased body weights and adiposity but only when fed a high-fat diet, suggesting there may be sex-differences in the central requirement for NMU2 in the control of food intake, body weight and adiposity [23]. More recently, selective knockdown of NMU2 in the PVN of rats using viral delivery of RNAi demonstrated that although food intake and body weight were unaffected in rats fed a standard diet, these rats consumed more food and gained significantly more weight when fed a high-fat diet. Knockdown also resulted in binge-type feeding on a high-fat diet and a preference for higher-fat food [8]. Overall, there is, therefore, clear evidence that NMU2 mediates the effects of centrally administered NmU and NmS and emerging evidence that the role of this system may be dependent on other influencing factors such as sex and diet.

Evidence is now emerging that NmU and particularly NMU2 may have a broader role in the CNS beyond the hypothalamus. For example, a genetic overexpression screen in zebrafish demonstrated that in larva, NmU promotes activity and suppresses sleep dependent on NMU2 and corticotropin releasing hormone at the level of the brainstem [14]. NMU2 is expressed in a variety of brain areas other then the hypothalamus, including areas related to reward. Indeed, intracerebroventricularly administered NmU reduces both amphetamine- and alcohol-induced accumbal dopamine release and increases in locomotor activity, highlighting a possible role in reward-related behaviours [132-133]. In line with a role of NMU2 in such actions is also the observation of presynaptic expression on GABA neurons in the nucleus accumbens shell where it has been reported to play a role in reducing cocaine-evoked hyperactivity [58].

Novel ligands

Both the poor pharmacokinetic characteristics of administered NmU and the possibility of receptor subtype-dependent physiological roles have driven the search for compounds with improved pharmacokinetics and NMU receptor subtype selectivity. A variety of approaches have been made to improve the stability of NmU including amino acid substitution, conjugation with, for example, polyethylene glycol and bovine serum albumin, truncation and a variety of other modifications including lipidation. Such changes have generated compounds with improved stability and in vivo activity [17,45-46,57,71,74,77,95,121-123]. Additionally, non-peptide compounds including flavonoid derivatives and p-synephrine (a protoalkaloid in bitter orange) have been identified as ligands [67,76,110,142]. Amongst both the non-peptide ligands and the modified peptide ligands, a number of compounds with selectivity for NMU receptor subtypes have been reported [67,71,76,110,121-122].

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