Journal article
Deficiency of RAMP1 Attenuates Antigen-Induced Airway Hyperresponsiveness in Mice
PloS one, Vol.9(7), pp.e102356-e102356
07/10/2014
DOI: 10.1371/journal.pone.0102356
PMCID: PMC4092148
PMID: 25010197
Abstract
Asthma is a chronic inflammatory disease affecting the lung, characterized by breathing difficulty during an attack following exposure to an environmental trigger. Calcitonin gene-related peptide (CGRP) is a neuropeptide that may have a pathological role in asthma. The CGRP receptor is comprised of two components, which include the G-protein coupled receptor, calcitonin receptor-like receptor (CLR), and receptor activity-modifying protein 1 (RAMP1). RAMPs, including RAMP1, mediate ligand specificity in addition to aiding in the localization of receptors to the cell surface. Since there has been some controversy regarding the effect of CGRP on asthma, we sought to determine the effect of CGRP signaling ablation in an animal model of asthma. Using gene-targeting techniques, we generated mice deficient for RAMP1 by excising exon 3. After determining that these mice are viable and overtly normal, we sensitized the animals to ovalbumin prior to assessing airway resistance and inflammation after methacholine challenge. We found that mice lacking RAMP1 had reduced airway resistance and inflammation compared to wildtype animals. Additionally, we found that a 50% reduction of CLR, the G-protein receptor component of the CGRP receptor, also ameliorated airway resistance and inflammation in this model of allergic asthma. Interestingly, the loss of CLR from the smooth muscle cells did not alter the airway resistance, indicating that CGRP does not act directly on the smooth muscle cells to drive airway hyperresponsiveness. Together, these data indicate that signaling through RAMP1 and CLR plays a role in mediating asthma pathology. Since RAMP1 and CLR interact to form a receptor for CGRP, our data indicate that aberrant CGRP signaling, perhaps on lung endothelial and inflammatory cells, contributes to asthma pathophysiology. Finally, since RAMP-receptor interfaces are pharmacologically tractable, it may be possible to develop compounds targeting the RAMP1/CLR interface to assist in the treatment of asthma.
Details
- Title: Subtitle
- Deficiency of RAMP1 Attenuates Antigen-Induced Airway Hyperresponsiveness in Mice
- Creators
- Manyu Li - University of North Carolina at Chapel HillSarah E. Wetzel-Strong - University of North Carolina at Chapel HillXiaoyang Hua - University of North Carolina at Chapel HillStephen L. Tilley - University of North Carolina at Chapel HillErin Oswald - University of California, San FranciscoMatthew F. Krummel - University of California, San FranciscoKathleen M. Caron - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.9(7), pp.e102356-e102356
- DOI
- 10.1371/journal.pone.0102356
- PMID
- 25010197
- PMCID
- PMC4092148
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 8
- Grant note
- U19AI077439 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) HD060860; DK99156 / National Institutes of Health/National Heart Lung and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases P01HL024136 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01DK099156 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01HD060860 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- Language
- English
- Date published
- 07/10/2014
- Academic Unit
- Otolaryngology
- Record Identifier
- 9984311440802771
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