G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation

Departments of 1 Medicine, 6 Biochemistry, 2 Cell Biology, 5 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710; 3 Department of Medicine, Ohio State University, Columbus, Ohio 43210; 4 School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley 6009, Western Australia, Australia; and 7 Departments of Physiology, Medicine and Pediatrics, Queen's University, Kingston, Ontario, Canada K7L 3N6 Submitted 25 July 2003 ; accepted in final form 5 October 2003 G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M 2 muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene ( GRK5 - / - ) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5 - / - and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from 2 -adrenergic receptor activation were diminished in GRK5 - / - mice. These data suggest that M 2 muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5 - / - mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease. transgenic mice; airway pressure time index; electric field stimulation; airway responsiveness Address for reprint requests and other correspondence: J. K. L. Walker, Box 2629, Duke Univ.