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Am J Physiol Gastrointest Liver Physiol 293: G36-G44, 2007. First published March 15, 2007; doi:10.1152/ajpgi.00464.2006
0193-1857/07 $8.00
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INFLAMMATION/IMMUNITY/MEDIATORS

Role of calcitonin receptor-like receptor in colonic motility and inflammation

Matthew S. Clifton, Julia J. Hoy, Jen Chang, Prema S. Idumalla, Humera Fakhruddin, Eileen F. Grady, Stephen Dada, Carlos U. Corvera, and Aditi Bhargava

Department of Surgery, University of California, San Francisco, California

Submitted 6 October 2006 ; accepted in final form 8 March 2007

Calcitonin gene-related peptide (CGRP) mediates neurogenic inflammation and modulates intestinal motility. The CGRP receptor is a heterodimer of calcitonin receptor-like receptor (CLR) and receptor-associated modifying protein 1. We used RNA interference to elucidate the specific role of CLR in colonic motility and inflammation. Intramural injection of double-stranded RNA (dsRNA) against CLR (dsCLR) into the colonic wall at two sites caused the spatial and temporal downregulation of CLR in the colon within 1 day of dsRNA injection. Knockdown of CLR persisted for 7–9 days, and the effect of knockdown spread to ~2 cm proximal and distal to the injection sites, whereas control dsRNA injection did not affect CLR expression. Measurement of isometric contractions of isolated colonic muscle segments revealed that in control dsRNA-injected rats, CGRP abrogated contractions entirely and decreased resting muscular tone, whereas in dsCLR-injected rats, CGRP decreased muscle tone but slow-wave contractions of varying amplitude persisted. In trinitrobenzene sulfonic acid-induced colitis, rats with knockdown of CLR displayed a significantly greater degree of edema and necrosis than saline- or control dsRNA-injected rats. Levels of the proinflammatory cytokines TNF-{alpha} and IL-6 were markedly upregulated by trinitrobenzene sulfonic acid treatment. TNF-{alpha} mRNA levels were further increased in CLR knockdown rats, whereas levels of IL-6 were unaltered. Thus this study demonstrates that CLR is a functional receptor for CGRP.

calcitonin gene-related peptide; RNA interference; trinitrobenzene sulfonic acid; cytokines; colon-specific; tumor necrosis factor-{alpha}


Address for reprint requests and other correspondence: A. Bhargava, Dept. of Surgery, Univ. of California San Francisco, 521 Parnassus Ave., Rm. S1268, Box 0660, San Francisco, CA 94143-0660 (e-mail: bhargavaa{at}surgery.ucsf.edu)






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