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Calcitonin Gene-Related Peptide: Role in Airway Homeostasis Azzeddine Dakhama1, Gary L Larsen2 and Erwin W Gelfand3

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Calcitonin Gene-Related Peptide: Role in Airway Homeostasis Azzeddine Dakhama1, Gary L Larsen2 and Erwin W Gelfand3 Calcitonin gene-related peptide: role in airway homeostasis Azzeddine Dakhama1, Gary L Larsen2 and Erwin W Gelfand3 The lung is an important source of sensory neuropeptides ily controlled by neural mechanisms, but underlying that modulate airway function in health and disease. Among inflammation and damage to airway structure can alter these neuropeptides, calcitonin gene-related peptide (CGRP) or interfere with this control [1]. plays a prominent role. CGRP is constitutively expressed in normal lungs where it localizes to a specialized subset of The lung is innervated by a rich supply of vagal nerve epithelial cells (neuroendocrine cells) and sensory C fibers afferent fibers, most of which are unmyelinated sensory C distributed to pulmonary airways, blood vessels and lymphoid fibers, with endings disseminated throughout the airways tissue. CGRP can mediate multiple effects, some of which have within the mucosa. Activation of afferent C fiber endings potential implications in airway homeostasis. These include by exposure to inhaled irritants or inflammatory stimuli vasoregulation, bronchoprotection, anti-inflammatory actions triggers the release of sensory neuropeptides and results and tissue repair. Targeting these effects of CGRP could be in the development of neurogenic inflammation in the a future avenue for modulation of certain aspects of airway airways [2]. This form of inflammation is characterized by diseases. increased vascular permeability, mucus hypersecretion and potentiation of airway smooth muscle contraction. Addresses These effects are normally terminated after proteolytic National Jewish Medical and Research Center, Department of degradation of effector sensory neuropeptides. Pediatrics, Denver, Colorado 80206, USA 1e-mail: [email protected] 2e-mail: [email protected] Among the variety of sensory neuropeptides that can be 3e-mail: [email protected] detected in the lung, calcitonin gene-related peptide (CGRP) is the most abundant. The fact that this neuro- peptide is constitutively expressed in normal airways Current Opinion in Pharmacology 2004, 4:215–220 implies a possible involvement in local homeostasis. This review comes from a themed issue on Recent studies suggest potential roles for CGRP in Respiratory pharmacology modulating airway function, vascular tone and inflam- Edited by Roy Goldie and Peter Henry matory immune responses. However, more studies are 1471-4892/$ – see front matter needed to further define the exact functions of CGRP in ß 2004 Elsevier Ltd. All rights reserved. health and disease and to prepare for evaluation of potential therapeutic targeting in human airway inflam- DOI 10.1016/j.coph.2004.01.006 matory diseases. Abbreviations Synthesis and metabolism of CGRP AHR airway hyperresponsiveness CGRP belongs to a family of related neuropeptides that AM adrenomedullin includes calcitonin (CT), adrenomedullin (AM) and amy- CGRP calcitonin gene-related peptide CRLR calcitonin receptor-like receptor lin [3]. CGRP is a 37 amino acid neuropeptide produced CT calcitonin by tissue-specific alternative processing of the mRNA NEBs neuroepithelial bodies transcript encoded by CT/CGRP gene [4–6]. There are PNEC pulmonary neuroendocrine cell two known isoforms of CGRP (a-CGRP and b-CGRP), RAMP receptor activity-modifying protein which differ by one amino acid in rats, and three in mouse RCP receptor component protein and humans (Table 1). Analyses of mRNA expression levels showed that a-CGRP is the most abundant form Introduction (> 80%) in the nervous system. The two isoforms are Although seeming to be protected anatomically, the encoded by separate gene loci located on chromosome 11 mammalian lung contains the largest surface area of in humans; however, their biological activities are indis- the body directly exposed to the environment. Mainte- tinguishable [7]. CGRP is susceptible to degradation by nance of airway homeostasis is a constant challenge in the neutral endopeptidase, which is abundant in the airway face of multiple disturbances that can be induced by epithelium. However, CGRP degraded at about 1.2% of pathogens (e.g. bacteria and viruses) and a variety of the rate of degradation for substance P in the presence of noxious environmental agents (e.g. allergens and pollu- recombinant neutral endopeptidase in vitro [8]. In the tants). These agents can reach the most distal parts of the presence of mast cell tryptase, CGRP degrades at faster lung and alter airway function, causing transient or per- rates comparable to those of other lung neuropeptides manent changes depending upon the susceptibility of the such as vasoactive intestinal peptide and peptide histi- exposed individual (Figure 1). Airway function is primar- dine-methionine [9]. www.sciencedirect.com Current Opinion in Pharmacology 2004, 4:215–220 216 Respiratory Figure 1 Environmental factors (pollutant, allergen, pathogen) Host factors (susceptibility, atopy) Damage Normal structure Altered structure Repair mucus Neurogenic inflammation PNEC nerve endings Edema, Mucus NEB ASM NEP, SP, NKA Tryptase CGRP, VIP BV Immune inflammation Cells Cytokines Spinal Mediators cord Normal function Altered function Current Opinion in Pharmacology Airway homeostasis is altered following exposure to noxious environmental factors in susceptible individuals. Damage inflicted to airway structure and activation of exposed sensory nerve endings by inhaled irritants and inflammatory mediators stimulate release of sensory neuropeptides, mediating neurogenic inflammation. Decreased neutral endopeptidase activity allows for unopposed actions by tackykinins (SP and NKA), causing increased mucus secretion, vascular leakage with plasma extravasation, and potentiation of airway smooth muscle contraction. Increased mast cell tryptase activity during an inflammatory response can cause degradation of CGRP and VIP, terminating their activities. Full recovery of homeostatic function requires complete and successful tissue repair. ASM, airway smooth muscle; BV, blood vessel; NKA, neurokinin-A; SP, substance P; VIP, vasoactive intestinal peptide. CGRP receptors and their signalling transfected into HEK293 cells, and not in COS-7 cells, pathways suggesting that other proteins (or co-receptors) are Two CGRP receptors have been identified pharmacolo- required for receptor function. A breakthrough came with gically on the basis of their differential affinities for the the discovery of receptor activity-modifying proteins competitive peptide antagonist CGRP8–37 [7]. CGRP1 (RAMPs), a novel family of single transmembrane receptors are more sensitive than CGRP2 receptors to domain receptors [12]. Three RAMPs have been cloned the antagonist CGRP8–37. Alternatively, the linear a- and characterized. When co-expressed with RAMP1 in a CGRP analogs [Cys(ACM)2,7]- and [Cys(Et)2,7]-CGRP, variety of cells, including COS-7 cells, CRLR functions as which are agonists with greater potency for CGRP2 than the CGRP1 receptor. When co-expressed with RAMP2 or for CGRP1 receptors, have also been used to distinguish RAMP3, CRLR functions as a receptor for AM, another between the two receptors. From the sequence of the member of the calcitonin family that is related to CGRP. calcitonin receptor, a candidate receptor was initially In addition, an intracellular accessory protein termed cloned by PCR in rat lung and was named calcitonin CGRP-receptor component protein (RCP) has recently receptor-like receptor (CRLR) [10]. Human CRLR has been identified and shown to be required for signal subsequently been cloned and proposed as the CGRP1 transduction through CGRP and AM receptors [13].A receptor [11]. However, CRLR was functional only when recent study identified a 66 kDa protein as a new receptor Table 1 Structure of CGRP isoforms in human, rat and mouse. Human a CGRP A C D TATCVTHRLAGLLSRSGGV VKN NFVPTNVGSKAF b CGRP A C N TATCVTHRLAGLLSRSGGM VKS NFVPTNVGSKAF Rat a CGRP S C N T A T C V T H R L A G L L S R S G G V V K D N F V P T N V G S E AF b CGRP S C N T A T C V T H R L A G L L S R S G G V V K D N F V P T N V G S K AF Mouse a CGRP S C N T A T C V T H R L A G LLSRSGGVV KDNFVPTN VGSEAF b CGRP S C N T A T C V T H R L A D LLSRSGGVL KDNFVPTD VGSEAF Bold characters denote distinct amino acids for a-andb-CGRP. Current Opinion in Pharmacology 2004, 4:215–220 www.sciencedirect.com Calcitonin gene-related peptide: role in airway homeostasis Dakhama, Larsen and Gelfand 217 for CGRP, which is distinct from CRLR and RAMP1 of functions, including neurotransmission, vasodilation [14 ], and proposed a new classification for CGRP1 and and immune regulation. CGRP is the most potent endo- CGRP2 receptors as CGRP-A and CGRP-B, respectively. genous vasodilator identified to date [3], and has been Binding of CGRP to its receptor is known to activate implicated in the regulation of vascular tone in the lungs, adenylyl cyclase and increase cAMP production, a path- where CGRP receptors are abundant in the bronchial way that involves Gas protein. Structure–function studies vessels [32]. CGRP attenuates the development of revealed that the first seven amino acids of the a-CGRP chronic hypoxic pulmonary hypertension in a rat model molecule interact with the transmembrane domain of [33]. In this animal model, chronic hypoxia has been CRLR and are required for receptor activation, whereas shown to increase cellular levels of CGRP in pulmonary residues 8–18 and 28–37 are necessary for high-affinity NEBs. In this context, pulmonary NEBs might function binding; residues 19–27 form a hinge region [15]. Struc- as chemoreceptors that sense altered oxygen levels dur- tural requirements for the interaction of CGRP with ing passage of air in the airways, with CGRP acting as a CGRP2 receptors are still unknown. regulatory mediator in the vascular response to hypoxia [34]. CGRP promotes epithelial cell proliferation in vitro Tissue distribution of CGRP and CGRP [27], and pulmonary NEBs can serve as an important receptors reservoir of progenitor cells during re-epithelialization of CGRP is distributed to central and peripheral nervous injured airways [35].AroleforCGRPintissuerepairis systems [16], and is present in sensory nerve fibers further supported by its capacity to induce migration and throughout the respiratory tract.
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