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A novel receptor for calcitonin gene-related peptide (CGRP) mediates secretion in the rat colon: implications for secretory function in colitis

TUBA ESFANDYARI, WALLACE K. MACNAUGHTON, RÉMI QUIRION^*, SERGE ST. PIERRE, JEAN-LOUIS JUNIEN and KEITH A. SHARKEY¹

Neuroscience and Gastrointestinal Research Groups, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1;
^* Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal, Quebec, Canada H4H 1R3;
Department of Chemistry, University of Quebec in Montreal, Montreal, Quebec, Canada H3C 3P8; and
Ferring Research Institute, Paris, France

¹Correspondence: Neuroscience Research Group, Department of Physiology and Biophysics, Health Sciences Centre, Room 2113, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alberta, Canada, T2N 4N1. E-mail: ksharkey{at}ucalgary.ca

The receptor responsible for CGRP-induced ion transport and permeability was examined in tissues from animals treated 7 days previously with trinitrobenzenesulfonic acid to induce colitis or in controls. CGRP caused a concentration-dependent increase in short circuit current (I_sc, EC₅₀ 21 nM), which was abolished in chloride-free buffer but was not blocked by CGRP_8–37 or tetrodotoxin (TTX). Amylin and adrenomedullin caused only a modest increase in I_sc. The responses to the linear CGRP₂ receptor agonists [Cys(Et)^2,7] hCGRP and [Cys(Acm)^2,7] hCGRP were considerably smaller than the response to CGRP. These responses were abolished in chloride-free buffer and were TTX sensitive. Atropine, doxantrazole, and indomethacin did not block the effects of CGRP or the CGRP₂ agonists. The response to [Cys(Et)^2,7] hCGRP was not affected by prior desensitization of the CGRP receptor and vice versa. Inflamed rats had a similar secretory response to CGRP (I_sc, EC₅₀ 15 nM) and [Cys(Et)^2,7] hCGRP as control tissues, while being hyporesponsive to carbachol. CGRP application increased electrical conductance of inflamed preparations. Taken together, these data suggest that CGRP may play an important role in the maintenance of host defense in colitis through an apparently novel CGRP receptor located on the colonic enterocyte.—Esfandyari, T., MacNaughton, W. K., Quirion, R., St. Pierre, S., Junien, J.-L., Sharkey, K. A. A novel receptor for calcitonin gene-related peptide (CGRP) mediates secretion in the rat colon: implications for secretory function in colitis.

Key Words: TNBS • ion transport • CGRP receptors • adrenomedullin • amylin • mast cells • secretion

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