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.

Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity

“…We confirmed the microarray findings by analyzing cell surface CALCRL expression on CD11b + dDCs by flow cytometry (Figure 6B). This is consistent with other reports showing expression of CGRP receptors by CD11b + DCs in other tissues (Li et al, 2014). …”

“…In the lung, these DCs also express CGRP receptors and promote airway hyperresponsiveness (Li et al, 2014). In murine vulvovaginal candidiasis, pain was accompanied by increased expression of CGRP in peripheral nerves (Farmer et al, 2011).…”

Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles

“…The knockout models display a range of phenotypic differences compared to WT mice. These include blood pressure and inflammatory phenotypes (31; 37; 38). Differences in wound healing, angiogenesis and lymphangiogenesis have also been reported, each of which was suppressed in the absence of RAMP1 (32).…”

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

“…RAMPs can also play important chaperoning roles for receptor trafficking processes, as noted not only for the canonical interaction with CLR, but also for the class C extracellular calcium-sensing receptor (CaSR) (Bouschet et al, 2005). Generation of genetically engineered mouse models in recent years has unmasked key roles for the different RAMP proteins in the cardiovasacular, renal, and respiratory systems, in addition to novel roles in inflammation (Kadmiel et al, 2012;Lenhart et al, 2013;Li et al, 2014). Importantly, the RAMP-receptor interface has emerged as a novel druggable pocket in its own right (Sexton et al, 2009Wootten et al, 2010).…”