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Updated: Sep 25, 2026
In vitro Functional Characterization of Mouse Colorectal Afferent Endings
Published on: January 21, 2015
Functional consequences of neuropeptide Y Y 2 receptor knockout and Y2 antagonism in mouse and human colonic tissues
Niall P Hyland1, Frida Sjöberg, Iain R Tough
1Centre for Neuroscience Research, King's College London, GKT School of Biomedical Sciences, Guy's Campus, London SE1 1UL, UK.
Abstract:
1 Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) differentially activate three Y receptors (Y(1), Y(2) and Y(4)) in mouse and human isolated colon. 2 The aim of this study was to characterise Y(2) receptor-mediated responses in colon mucosa and longitudinal smooth muscle preparations from wild type (Y(2)+/+) and knockout (Y(2)-/-) mice and to compare the former with human mucosal Y agonist responses. Inhibition of mucosal short-circuit current and increases in muscle tone were monitored in colonic tissues from Y(2)+/+ and Y(2)-/- mice+/-Y(1) ((R)-N-[[4-(aminocarbonylaminomethyl)phenyl)methyl]-N(2)-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304) or Y(2) (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide (BIIE0246) antagonists. 3 Predictably, Y(2)-/- tissues were insensitive to Y(2)-preferred agonist PYY(3-36) (
Insights
Neuropeptide Y (NPY) and peptide YY (PYY) Y(2) receptors in the colon regulate ion transport and muscle contraction. Blocking these receptors impacts submucosal neurons, affecting gut function in mice and humans.
Area of Science:
- Gastroenterology
- Neuroscience
- Pharmacology
Background:
- Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are key regulators of gastrointestinal function.
- These peptides exert their effects through distinct Y receptors (Y(1), Y(2), Y(4)) in the colon.
- Understanding Y receptor-specific roles is crucial for deciphering colonic physiology and pathophysiology.
Purpose of the Study:
- To characterize Y(2) receptor-mediated responses in mouse and human colon preparations.
- To compare Y(2) receptor functions in colonic mucosa and longitudinal smooth muscle.
- To investigate the role of Y(2) receptors in regulating ion transport and muscle tone.
Main Methods:
- Utilized wild-type (Y(2)+/+) and knockout (Y(2)-/-) mice for comparative studies.
- Employed Y(1) and Y(2) receptor-specific antagonists (BIBO3304 and BIIE0246, respectively).
- Measured mucosal short-circuit current and longitudinal muscle tone in isolated colonic tissues.
- Assessed the impact of tetrodotoxin to identify neuronal involvement.
Main Results:
- Y(2) receptor knockout mice were insensitive to the Y(2)-preferred agonist PYY(3-36).
- Y(2) receptor antagonists modulated mucosal ion transport and smooth muscle tone in a receptor-dependent manner.
- Y(2) receptors were localized to submucosal neurons, influencing ion transport, and to longitudinal muscle, mediating contraction.
Conclusions:
- Tonic activation of submucosal Y(2) receptors by endogenous peptides can indirectly reduce colonic ion transport.
- Direct activation of Y(2) receptors on longitudinal muscle leads to colonic contraction.
- These findings highlight the significant role of Y(2) receptors in regulating both mucosal and smooth muscle functions in the colon.
