Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery

Neuropeptide Y (NPY) is the most abundant peptide present in the mammalian central and peripheral nervous system. NPY exhibits a variety of potent central and peripheral effects including those on feeding, memory, blood pressure, cardiac contractility and intestinal secretions. Classical pharmacological studies have shown that NPY effects are mediated by four different receptor subtypes, Y-1, Y-1-like, Y-2, and Y-3. However, the existence of numerous atypical activities provide strong evidence for the occurrence of additional NPY receptor subtypes. Pharmacological studies have further been facilitated by the recent cloning and expression of Y-1, Y-2, Y-4 (PP-1) and Y-5 receptors. Moreover, the cloned Y-5 receptor has been suggested to be the long awaited Y-1-like receptor involved in feeding. Structure-activity studies have laid a good foundation towards the development of receptor selective compounds, and to date potent Y-1 selective peptide and nonpeptide antagonists have been developed. The need to clone numerous receptor subtypes and to develop receptor selective compounds for physiological and perhaps clinical use is expected to keep NPY research active for many years to come.