Point-mutation studies have revealed that changes in amino acid sequence may alter binding of NmU to its receptors, NMUR1 and NMUR2; for example, substitution of certain residues may not affect NmU activity at NMUR2, but reduces the response mediated by NMUR1 (13).
Moreover, NmS binds to NmU receptors NMUR1 and NMUR2, with some data suggesting that NMUR2 has higher affinity for NmS than for NmU (16).
Two different receptors exist for NmU, termed NMUR1 (also known as GPR66 and FM-3) and NMUR2 (also known as TGR-1 and FM-4), encoded by genes located in human chromosomes 2 and 5, respectively (14, 28, 29, 35-39).
Most studies agree that NMUR1 is preferentially expressed in the periphery, particularly in the gastrointestinal tract, while NMUR2 is predominantly expressed in the central nervous system (41).
It should be noted that NmU has also been shown to act independently of NMUR1 and NMUR2.
NmU binding to NMUR1 and NMUR2 results in increased intracellular [Ca.sup.2+] mediated by phospholipase C activation (13, 14, 28, 29, 35-39).
Studies with mice deficient in NmU receptors have shown that gastrointestinal smooth muscle contraction is likely mediated by NMUR1, because contraction is unaffected in [Nmur2.sup.-/-] mice but compromised in [Nmur1.sup.-/-] mice (53, 54).
However, mice deficient in NMUR2 do not reproduce the phenotype of [NmU.sup.-/-] mice, showing no obesity, hyperphagia, or reduced energy expenditure; this was explained by suggesting that [proNMU.sub.104-136] mediates this effect through a different receptor, either NMUR1 or a yet unidentified receptor (6).
On the other hand, peripheral administration of NmU improved glucose tolerance (90); these results are in stark contrast with the inhibitory effects of NmU in pancreatic insulin secretion, which appears to be mediated by somatostatin and NMUR1 (92, 93), and the observed increase in insulin levels in [NmU.sup.-/-] mice (73).
NmU mRNA has been detected in antigen-presenting cells, particularly monocytes and dendritic cells, and NMUR1 mRNA has been detected in T and natural killer cells, and also at lower concentrations in other immune and hematopoietic cells such as eosinophils and mast cells (14, 122), suggesting a role in the immune response.
Binding of NmU to NMUR1 present in mast cells induced their degranulation, resulting in vasodilation, edema, and neutrophil infiltration (33).