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

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Abstract
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 (Isc) continuously recorded. Basolateral PYY, NPY, human PP (hPP), PYY(3 – 36), [Leu31, Pro34]PYY (Pro34PYY) and [Leu31, Pro34]‐NPY (Pro34NPY) all reduced basal Isc in untreated colon. Of all the Y agonists tested PYY(3 – 36) responses were most sensitive to tetrodotoxin (TTX) pretreatment, indicating that Y2‐receptors are located on intrinsic neurones as well as epithelia in this tissue. The EC50 values for Pro34PYY, 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 Y5 agonist [Ala31, Aib32]‐NPY had no effect at 100 nM. Y1 receptor antagonists, BIBP3226 and BIBO3304 both increased basal Isc levels per se and inhibited subsequent PYY and Pro34PYY but not hPP or PYY(3 – 36) responses. The Y2 antagonist, BIIE0246 also raised basal Isc levels and attenuated subsequent PYY(3 – 36) but not Pro34PYY or hPP responses. We conclude that Y1 and Y2 receptor‐mediated inhibitory tone exists in human colon mucosa. PYY and NPY exert their effects via both Y1 and Y2 receptors, but the insensitivity of hPP responses to either Y1 or Y2 antagonism, or to TTX, indicates that Y4 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

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