Neuropeptide Y, Y 1 , Y 2 and Y 4 receptors mediate Y agonist responses in isolated human colon mucosa

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. 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. The EC 50 values for Pro 34 PYY, PYY(3 – 36) and hPP were 9.7 n M (4.0 – 23.5), 11.4 n M (7.6 – 17.0) and 14.5 n M (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 n M . 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. 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. British Journal of Pharmacology (2001) 135 , 1505–1512; doi: 10.1038/sj.bjp.0704604