Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats

L. Antonioli; M. Fornai; O. Awwad; G. Giustarini; C. Pellegrini; M. Tuccori; V. Caputi; M. Qesari; I. Castagliuolo; P. Brun; M.C. Giron; C. Scarpignato; C. Blandizzi; R. Colucci

doi:10.1111/bph.12539

Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats

L. Antonioli, M. Fornai, O. Awwad, G. Giustarini, C. Pellegrini, M. Tuccori, V. Caputi, M. Qesari, I. Castagliuolo, P. Brun, M.C. Giron, C. Scarpignato, C. Blandizzi, R. Colucci

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

Abstract

Background and Purpose: Adenosine A2Breceptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2Breceptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach: Colitis was induced by 2,4- dinitrobenzenesulfonic acid (DNBS). Colonic A2Breceptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2Breceptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2Breceptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results: A2Breceptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2Breceptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2Breceptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2Breceptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2Breceptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications: Under normal conditions, endogenous adenosine modulates colonic motility via A2Breceptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2Breceptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2Breceptor activation. © 2013 The British Pharmacological Society.

Original language	English
Pages (from-to)	1314-1329
Number of pages	16
Journal	British Journal of Pharmacology
Volume	171
Issue number	5
DOIs	https://doi.org/10.1111/bph.12539
Publication status	Published - 1 Mar 2014
Externally published	Yes

Keywords

A2Breceptor
adenosine
colitis
colonic neuromuscular contractions
adenosine 5' (n ethylcarboxamide)
adenosine A2b receptor
adenosine deaminase
carbachol
dinitrobenzenesulfonic acid
messenger RNA
n (4 cyanophenyl) 2 [4 (2,3,6,7 tetrahydro 2,6 dioxo 1,3 dipropyl 1h purin 8 yl)phenoxy]acetamide
sulfonic acid derivative
unclassified drug
animal experiment
animal model
animal tissue
article
cholinergic activity
controlled study
disease association
immunofluorescence
immunoprecipitation
intestinal dysmotility
male
neuromuscular function
nonhuman
priority journal
protein determination
protein expression
protein function
protein localization
protein protein interaction
rat
reverse transcription polymerase chain reaction

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10.1111/bph.12539

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Antonioli, L., Fornai, M., Awwad, O., Giustarini, G., Pellegrini, C., Tuccori, M., Caputi, V., Qesari, M., Castagliuolo, I., Brun, P., Giron, M. C., Scarpignato, C., Blandizzi, C., & Colucci, R. (2014). Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats. British Journal of Pharmacology, 171(5), 1314-1329. https://doi.org/10.1111/bph.12539

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title = "Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats",

abstract = "Background and Purpose: Adenosine A2Breceptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2Breceptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach: Colitis was induced by 2,4- dinitrobenzenesulfonic acid (DNBS). Colonic A2Breceptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2Breceptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2Breceptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results: A2Breceptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2Breceptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2Breceptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2Breceptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2Breceptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications: Under normal conditions, endogenous adenosine modulates colonic motility via A2Breceptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2Breceptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2Breceptor activation. {\textcopyright} 2013 The British Pharmacological Society.",

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author = "L. Antonioli and M. Fornai and O. Awwad and G. Giustarini and C. Pellegrini and M. Tuccori and V. Caputi and M. Qesari and I. Castagliuolo and P. Brun and M.C. Giron and C. Scarpignato and C. Blandizzi and R. Colucci",

year = "2014",

month = mar,

day = "1",

doi = "10.1111/bph.12539",

language = "English",

volume = "171",

pages = "1314--1329",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley-Blackwell",

number = "5",

}

Antonioli, L, Fornai, M, Awwad, O, Giustarini, G, Pellegrini, C, Tuccori, M, Caputi, V, Qesari, M, Castagliuolo, I, Brun, P, Giron, MC, Scarpignato, C, Blandizzi, C & Colucci, R 2014, 'Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats', British Journal of Pharmacology, vol. 171, no. 5, pp. 1314-1329. https://doi.org/10.1111/bph.12539

TY - JOUR

T1 - Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats

AU - Antonioli, L.

AU - Fornai, M.

AU - Awwad, O.

AU - Giustarini, G.

AU - Pellegrini, C.

AU - Tuccori, M.

AU - Caputi, V.

AU - Qesari, M.

AU - Castagliuolo, I.

AU - Brun, P.

AU - Giron, M.C.

AU - Scarpignato, C.

AU - Blandizzi, C.

AU - Colucci, R.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Background and Purpose: Adenosine A2Breceptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2Breceptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach: Colitis was induced by 2,4- dinitrobenzenesulfonic acid (DNBS). Colonic A2Breceptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2Breceptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2Breceptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results: A2Breceptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2Breceptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2Breceptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2Breceptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2Breceptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications: Under normal conditions, endogenous adenosine modulates colonic motility via A2Breceptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2Breceptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2Breceptor activation. © 2013 The British Pharmacological Society.

AB - Background and Purpose: Adenosine A2Breceptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2Breceptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach: Colitis was induced by 2,4- dinitrobenzenesulfonic acid (DNBS). Colonic A2Breceptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2Breceptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2Breceptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results: A2Breceptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2Breceptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2Breceptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2Breceptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2Breceptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications: Under normal conditions, endogenous adenosine modulates colonic motility via A2Breceptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2Breceptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2Breceptor activation. © 2013 The British Pharmacological Society.

KW - A2Breceptor

KW - adenosine

KW - colitis

KW - colonic neuromuscular contractions

KW - adenosine 5' (n ethylcarboxamide)

KW - adenosine A2b receptor

KW - adenosine deaminase

KW - carbachol

KW - dinitrobenzenesulfonic acid

KW - messenger RNA

KW - n (4 cyanophenyl) 2 [4 (2,3,6,7 tetrahydro 2,6 dioxo 1,3 dipropyl 1h purin 8 yl)phenoxy]acetamide

KW - sulfonic acid derivative

KW - unclassified drug

KW - animal experiment

KW - animal model

KW - animal tissue

KW - article

KW - cholinergic activity

KW - controlled study

KW - disease association

KW - immunofluorescence

KW - immunoprecipitation

KW - intestinal dysmotility

KW - male

KW - neuromuscular function

KW - nonhuman

KW - priority journal

KW - protein determination

KW - protein expression

KW - protein function

KW - protein localization

KW - protein protein interaction

KW - rat

KW - reverse transcription polymerase chain reaction

U2 - 10.1111/bph.12539

DO - 10.1111/bph.12539

M3 - Article

SN - 0007-1188

VL - 171

SP - 1314

EP - 1329

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 5

ER -

Role of the A2Breceptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats

Abstract

Keywords

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