Functional consequences of neuropeptide Y Y 2 receptor knockout and Y 2 antagonism in mouse and human colonic tissues

Niall P. Hyland; Frida Sjöberg; Iain R. Tough; Herbert Herzog; Helen M. Cox

doi:10.1038/sj.bjp.0705298

Functional consequences of neuropeptide Y Y ₂ receptor knockout and Y ₂ antagonism in mouse and human colonic tissues

Niall P. Hyland
, Frida Sjöberg
, Iain R. Tough
, Herbert Herzog
, Helen M. Cox

Research output: Contribution to journal › Article › peer-review

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) (≤ 100 nM), but unexpectedly Y ₄-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y ₂-/- mice (Sainsbury et al., 2002). 4. BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y ₂+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y ₂-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y ₂+/+ basal tone. BIBO3304 abolished residual Y ₁-mediated NPY responses in Y ₂-/- smooth muscle. 5. Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y ₂+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y ₂ receptors are located on submucosal, but not myenteric neurones. 6. Tonic activation of submucosal Y ₂ receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y ₂ receptors on longitudinal muscle results in contraction.

Original language	English
Pages (from-to)	863-871
Number of pages	9
Journal	British Journal of Pharmacology
Volume	139
Issue number	4
DOIs	https://doi.org/10.1038/sj.bjp.0705298
Publication status	Published - Jun 2003
Externally published	Yes

Keywords

Mouse and human colon
Mucosal ion transport
Neuropeptide Y receptors
Pancreatic polypeptides
Smooth muscle contraction

Access to Document

10.1038/sj.bjp.0705298

Cite this

@article{478aa929b12342df9d142733270b88d5,

title = "Functional consequences of neuropeptide Y Y 2 receptor knockout and Y 2 antagonism in mouse and human colonic tissues",

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) (≤ 100 nM), but unexpectedly Y 4-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y 2-/- mice (Sainsbury et al., 2002). 4. BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y 2+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y 2-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y 2+/+ basal tone. BIBO3304 abolished residual Y 1-mediated NPY responses in Y 2-/- smooth muscle. 5. Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y 2+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y 2 receptors are located on submucosal, but not myenteric neurones. 6. Tonic activation of submucosal Y 2 receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y 2 receptors on longitudinal muscle results in contraction.",

keywords = "Mouse and human colon, Mucosal ion transport, Neuropeptide Y receptors, Pancreatic polypeptides, Smooth muscle contraction",

author = "Hyland, \{Niall P.\} and Frida Sj{\"o}berg and Tough, \{Iain R.\} and Herbert Herzog and Cox, \{Helen M.\}",

year = "2003",

month = jun,

doi = "10.1038/sj.bjp.0705298",

language = "English",

volume = "139",

pages = "863--871",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc",

number = "4",

}

TY - JOUR

T1 - Functional consequences of neuropeptide Y Y 2 receptor knockout and Y 2 antagonism in mouse and human colonic tissues

AU - Hyland, Niall P.

AU - Sjöberg, Frida

AU - Tough, Iain R.

AU - Herzog, Herbert

AU - Cox, Helen M.

PY - 2003/6

Y1 - 2003/6

N2 - 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) (≤ 100 nM), but unexpectedly Y 4-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y 2-/- mice (Sainsbury et al., 2002). 4. BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y 2+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y 2-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y 2+/+ basal tone. BIBO3304 abolished residual Y 1-mediated NPY responses in Y 2-/- smooth muscle. 5. Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y 2+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y 2 receptors are located on submucosal, but not myenteric neurones. 6. Tonic activation of submucosal Y 2 receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y 2 receptors on longitudinal muscle results in contraction.

AB - 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) (≤ 100 nM), but unexpectedly Y 4-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y 2-/- mice (Sainsbury et al., 2002). 4. BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y 2+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y 2-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y 2+/+ basal tone. BIBO3304 abolished residual Y 1-mediated NPY responses in Y 2-/- smooth muscle. 5. Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y 2+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y 2 receptors are located on submucosal, but not myenteric neurones. 6. Tonic activation of submucosal Y 2 receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y 2 receptors on longitudinal muscle results in contraction.

KW - Mouse and human colon

KW - Mucosal ion transport

KW - Neuropeptide Y receptors

KW - Pancreatic polypeptides

KW - Smooth muscle contraction

UR - https://www.scopus.com/pages/publications/0038678675

U2 - 10.1038/sj.bjp.0705298

DO - 10.1038/sj.bjp.0705298

M3 - Article

C2 - 12813010

AN - SCOPUS:0038678675

SN - 0007-1188

VL - 139

SP - 863

EP - 871

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 4

ER -

Functional consequences of neuropeptide Y Y ₂ receptor knockout and Y ₂ antagonism in mouse and human colonic tissues

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this