title: Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice.
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.
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Manyu
authors.initials: M
authors.lastname: Li
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wetzel-Strong
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Hua
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Tilley
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Oswald
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Caron
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D058286:Calcitonin Receptor-Like Protein; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D015740:Calcitonin Gene-Related Peptide