Review Monomeric G-proteins as signal transducers in airway physiology and pathophysiology Dedmer Schaafsma a,b, ⁎, Sara S.Roscioni c , Herman Meurs c , Martina Schmidt c, ⁎ a Departments of Physiology & Internal Medicine, and Section of Respiratory Disease, University of Manitoba, Winnipeg,Manitoba,Canada b Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg,Manitoba,Canada c Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands A B S T R A C T A R T I C L E I N F O Article history: Received 7 March 2008 Accepted 23 April 2008 Available online 1 May 2008 Keywords: Allergic asthma Airway hyperresponsiveness Airway inflammation Monomeric G-proteins Epac Rho kinase Monomeric G-proteins,also referred to as smallGTPases,function as biologicalhubs being activated by extracellular stimuli and regulate downstream signalling events, which result in different cellular responses. The importance of these mechanisms is mirrored by the fact that several pathological conditions, including allergic asthma, are associated with derailed GTPases signalling. For this reason attention has been focused on the role of monomeric G-proteins and their effectors in airway (patho)physiology. In this article we review our current knowledge on the regulation and functions of Ras and Rho GTPase signalling under physiologica and pathophysiological conditions in the pulmonary system. Based on recent findings concerning novel regulatory proteins for Ras family members, we further discuss potential future directions for therapeutical interventions in asthma. © 2008 Elsevier Inc. All rights reserved. Contents 1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1705 2. Regulation of monomeric G-proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1706 3. Airway smooth muscle contraction: ex vivo and in vivo contractile responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707 4. Airway inflammation: migration, infiltration and endothelial barrier function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707 5. Airway remodelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1708 5.1. Airway smooth muscle hyperplasia, hypertrophy and migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1708 5.2. Airway smooth muscle phenotype plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1710 5.3. Airway wall fibrosis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1711 6. Potential new targets and future directions? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712 7. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1713 Acknowledgements .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1713 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1713 1. Introduction Allergic asthma is a chronic inflammatory airway disease char- acterized by allergen-induced early and late bronchial obstructive reactions,associated with infiltration and activation of inflammatory cells in the airways and the development of airway hyperresponsive- ness (AHR) to a variety of stimuli,including neurotransmitters and inflammatory mediators that are being released during an allergic reaction[1]. The development of AHR is importantly determined by Cellular Signalling 20 (2008) 1705–1714 ⁎ Corresponding authors.Schaafsma isto be contacted at the Departmentsof Physiology & Internal Medicine, and Section of Respiratory Disease, University of Manitoba,Winnipeg,Manitoba,Canada.Schmidt,Department of Molecular Pharma- cology,University of Groningen,Antonius Deusinglaan 1,9713 AV Groningen,The Netherlands. Tel.: +31 50 363 3322; fax: +31 50 363 6908. E-mail address: M.Schmidt@rug.nl (M. Schmidt). 0898-6568/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2008.04.012 Contents lists available at ScienceDirect Cellular Signalling j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c e l l s i g