%0 Journal Article
%T Muscarinic Receptors and Their Antagonists in COPD: Anti-Inflammatory and Antiremodeling Effects
%A George Karakiulakis
%A Michael Roth
%J Mediators of Inflammation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/409580
%X Muscarinic receptors are expressed by most cell types and mediate cellular signaling of their natural ligand acetylcholine. Thereby, they control numerous central and peripheral physiological organ responses to neuronal activity. In the human lung, muscarinic receptors are predominantly expressed by smooth muscle cells, epithelial cells, and fibroblasts. Antimuscarinic agents are used for the treatment of chronic obstructive pulmonary disease and to a lesser extent for asthma. They are primarily used as bronchodilators, but it is now accepted that they are also associated with anti-inflammatory, antiproliferative, and antiremodeling effects. Remodeling of the small airways is a major pathology in COPD and impairs lung function through changes of the extracellular matrix. Glycosaminoglycans, particularly hyaluronic acid, and matrix metalloproteases are among extracellular matrix molecules that have been associated with tissue inflammation and remodeling in lung diseases, including chronic obstructive pulmonary disease and asthma. Since muscarinic receptors have been shown to influence the homeostasis of glycosaminoglycans and matrix metalloproteases, these molecules may be proved valuable endpoint targets in clinical studies for the pharmacological exploitation of the anti-inflammatory and antiremodeling effects of muscarinic inhibitors in the treatment of chronic obstructive pulmonary disease and asthma. 1. Muscarinic Receptors The muscarinic receptors are metabotropic receptors that may be linked to plasma membrane or ion channels [1, 2]. They belong to the superfamily of rhodopsin-like, seven transmembrane domains, single-glycoprotein receptors that are connected by intra- and extracellular loops. Muscarinic receptors initiate intracellular responses via interaction with GTP-binding proteins (G-proteins), although activation of other signaling molecules has been reported [1, 3, 4]. There are five subtypes of muscarinic receptors, referred to as M1 to M5, based on the order of their discovery, and according to the nomenclature proposed by Caulfield and Birdsall [5]. Muscarinic receptors are symbolized in the literature as ˇ°M1 mAChR,ˇ± ˇ°M1-mAChR,ˇ± ˇ°m1AChR,ˇ± or ˇ°mAChR1ˇ± for the M1 receptor. In this paper muscarinic receptor subtypes will be referred to as M1, M2, M3, M4, and M5, according to IUPHAR [6] and the MeSH Browser [7] of the National Library of Medicine of the National Institute of Health, USA. Molecular cloning revealed that the five muscarinic receptors are encoded by separate intronless human genes. The muscarinic receptor gene sequences have
%U http://www.hindawi.com/journals/mi/2012/409580/