Neuropeptide Y receptors; antisecretory control of intestinal epithelial function

This paper reviews the cellular localisation, mechanisms of release and intestinal absorptive actions of neuropeptide Y and its related peptides, peptide YY, pancreatic polypeptide and major fragments NPY(3-36) and PYY(3-36). While NPY is commonly found in inhibitory enteric neurons that can be interneurons, motor neurons or secretomotor-nonvasodilator in nature, its analogue, peptide YY in contrast, is located in neuroendocrine L-cells that predominate in the colorectal mucosa. Peptide YY is released from these cells when nutrients arrive in the small or large bowel, exerting paracrine as well as hormonal actions. Pancreatic polypeptide is found in relatively few, scattered intestinal endocrine cells, the majority of this peptide being produced by, and released from pancreatic islet F-cells in response to food intake. An introduction to the current pharmacology of this family of peptides is provided and the different types of neuropeptide Y (termed Y) receptors, their agonist preferences, antagonism, and preferred signalling pathways, are described. Our current understanding of specific Y receptor localisation within the intestine as determined by immunohistochemistry, is presented as a prelude to an assessment of functional studies that have monitored ion transport across isolated mucosal preparations. It is becoming clear that three Y receptor types are significant functionally in human colon, as well as particular rodent models (e.g. mouse) and these, namely the Y(1), Y(2) and Y(4) receptors, are discussed in detail. Their presence within the basolateral aspect of the epithelial layer (Y(1) and Y(4) receptors) or on enteric neurons (Y(1) and Y(2) receptors) and their activation by endogenous neuropeptide Y, peptide YY (Y(1) and Y(2) receptors) or pancreatic polypeptide (which prefers Y(4) receptors) results consistently in antisecretory/absorptive responses. The recent use of novel mouse knockouts has helped establish loss of specific intestinal functions including Y(1) and Y(2) receptor-mediated absorptive tone in colon mucosa. Progress in this field has been rapid recently, aided by the availability of selective antagonists and mutant mice lacking either one (e.g. Y(4)-/-, for which no antagonists exist at present) or more Y receptor types. It is therefore timely to review this work and present a rational basis for developing stable synthetic Y receptor agonists as novel anti-diarrhoeals.