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

Abstract

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 approximately 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.

• Authors: Matthew S Clifton, Julia J Hoy, Jen Chang, Prema S Idumalla, Humera Fakhruddin, Eileen F Grady, Stephen Dada, Carlos U Corvera, Aditi Bhargava
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 293 Issue 1 Pg. G36-44 (Jul 2007) ISSN: 0193-1857 [Print] United States
• PMID: 17363466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcitonin Receptor-Like Protein
• RNA, Double-Stranded
• Receptors, Calcitonin
• Trinitrobenzenesulfonic Acid
• Calcitonin Gene-Related Peptide

Topics

• Animals
• Calcitonin Gene-Related Peptide (metabolism)
• Calcitonin Receptor-Like Protein
• Colitis (chemically induced, physiopathology)
• Colon (physiology)
• Gastrointestinal Motility (physiology)
• Male
• RNA Interference
• RNA, Double-Stranded (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcitonin (physiology)
• Trinitrobenzenesulfonic Acid