Neuropeptide Y (NPY) receptors are activated by the endogenous peptides neuropeptide Y (NPY), NPY-(3-36), peptide YY (PYY), PYY-(3-36) and pancreatic polypeptide (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine receptor. The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene. NPY in mammals is primarily synthesized and released by neurons, which in the peripheral nervous system are predominantly sympathetic neurons. PYY is predominantly synthesized and released by intestinal endocrine cells, and can also coexist with glucagon in pancreatic acini and enteroglucagon in endocrine cells of the lower bowel. PP is mainly found in pancreatic cells distinct from those storing insulin, glucagon or somatostatin. However, in some cases other cell types can also express NPY, PYY and PP. While NPY acts as a neurotransmitter, PYY and PP in mammals act as hormones. Physiological effects attributed to NPY include stimulation of food intake, inhibition of anxiety in the CNS, presynaptic inhibition of neurotransmitter release in the CNS and periphery, modulation of circadian rhythm, release of pituitary hormones, pain transmission. Physiological effects attributed to PYY include slowing of intestinal transit, inhibition of gastrointestinal anion and electrolyte secretion and appetite inhibition. Physiological effects attributed to PP include appetite stimulation. At present five distinct NPY receptors have been established by receptor cloning studies. With regard to endogenous agonists, the receptors Y1, Y2 and Y5 preferentially bind NPY and PYY, whereas the Y4 receptor preferentially binds PP; relative to Y1 and Y4 receptors, the Y2 and Y5 receptors are also potently activated by NPY3-36 and PYY3-36. All NPY receptors couple to pertussis toxin-sensitive G proteins of the Gi or Go family.