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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/G337    most recent 00112.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Buresi, M. C. Articles by MacNaughton, W. K. Search for Related Content PubMed PubMed Citation Articles by Buresi, M. C. Articles by MacNaughton, W. K.

NEUROREGULATION AND MOTILITY

Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro

¹Mucosal Inflammation and ²Gastrointestinal Research Groups, University of Calgary, Calgary, Alberta, Canada; ³Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania; ⁴Dipartimento di Farmacologia Sperimentale, University of Naples; and ⁵Dipartimento di Chimica Farmaceutica e Tossicologica, University of Naples, Italy

Submitted 11 March 2004 ; accepted in final form 31 August 2004

The proteinase-activated thrombin receptor-1 (PAR-1) belongs to a unique family of G protein-coupled receptors activated by proteolytic cleavage. We studied the effect of PAR-1 activation in the regulation of ion transport in mouse colon in vitro. Expression of PAR-1 in mouse colon was assessed by RT-PCR and immunohistochemistry. To study the role of PAR-1 activation in chloride secretion, mouse colon was mounted in Ussing chambers. Changes in short-circuit current (I_sc) were measured in tissues exposed to either thrombin, saline, the PAR-1-activating peptide TFLLR-NH₂, or the inactive reverse peptide RLLFT-NH₂, before electrical field stimulation (EFS). Experiments were repeated in the presence of either a PAR-1 antagonist or in PAR-1-deficient mice to assess receptor specificity. In addition, studies were conducted in the presence of chloride-free buffer or the muscarinic antagonist atropine to assess chloride dependency and the role of cholinergic neurons in the PAR-1-induced effect. PAR-1 mRNA was expressed in full-thickness specimens and mucosal scrapings of mouse colon. PAR-1 immunoreactivity was found on epithelial cells and on neurons in submucosal ganglia where it was colocalized with both VIP and neuropeptide Y. After PAR-1 activation by thrombin or TFLLR-NH₂, secretory responses to EFS but not those to forskolin or carbachol were significantly reduced. The reduction in the response to EFS was not observed in the presence of the PAR-1 antagonist, in PAR-1-deficient mice, when chloride was excluded from the bathing medium, or when atropine was present. PAR-1 is expressed in submucosal ganglia in the mouse colon and its activation leads to a decrease in neurally evoked epithelial chloride secretion.

enteric nervous system; epithelial ion transport; thrombin; submucosal secretomotor neurons

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