Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa

1 The aim of this study was to provide a pharmacological characterization of the Y receptor types responsible for neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) effects upon electrogenic ion transport in isolated human colonic mucosa. 2 Preparations of descending colon were voltage-clamped at 0 mV in Ussing chambers and changes in short-circuit current (I-sc) continuously recorded. Basolateral PYY, NPY, human PP (hPP), PYY(3-36), [Leu(31), Pro(34)]PYY (Pro(34)PYY) and [Leu(31), Pro(34)]-Npy (Pro(34)NPY) all reduced basal I-sc in untreated colon. Of all the Y agonists tested PYY(3-36) responses were most sensitive to tetrodotoxin (TTX) pretreatment, indicating that Y-2-receptors are located on intrinsic neurones as well as epithelia in this tissue. 3 The EC50 values for Pro(34)pyy, PYY(3-36) and hPP were 9.7 nM (4.0-23.5), 11.4 nM (7.6-17.0) and 14.5 nM (10.2-20.5) and response curves exhibited similar efficacies. The novel Y-5 agonist [Ala(31), Aib(32)]-NPY had no effect at 100 nM. 4 Y-1 receptor antagonists, BIBP3226 and BIBO3304 both increased basal I-sc levels per se and inhibited subsequent PYY and Pro(34)PYY but not hPP or PYY(3-36) responses. The Y-2 antagonist, BIIE0246 also raised basal I-sc levels and attenuated subsequent PYY(3-36) but not Pro(34)PYY or hPP responses. 5 We conclude that Y-1 and Y-2 receptor-mediated inhibitory tone exists in human colon mucosa. PYY and NPY exert their effects via both Y-1 and Y-2 receptors, but the insensitivity of hPP responses to either Y-1 or Y-2 antagonism, or to TTX, indicates that Y-4 receptors are involved and that they are predominantly post-junctional in human colon.