Role of calcitonin receptor-like receptor in colonic motility and inflammation.
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.
Clifton
Matthew S
MS
Department of Surgery, University of California-San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.
Hoy
Julia J
JJ
Chang
Jen
J
Idumalla
Prema S
PS
Fakhruddin
Humera
H
Grady
Eileen F
EF
Dada
Stephen
S
Corvera
Carlos U
CU
Bhargava
Aditi
A
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D058286:Calcitonin Receptor-Like Protein; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000502:physiology*; D008297:Male; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid
D058286:Calcitonin Receptor-Like Protein; D012330:RNA, Double-Stranded; D018003:Receptors, Calcitonin; D014302:Trinitrobenzenesulfonic Acid; D015740:Calcitonin Gene-Related Peptide