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1 Department of Medicine, Duke University Medical Center, Durham, NC, USA
2 Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
3 Department of Medicine, Ohio State University, Columbus, OH, USA
4 School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, WA, Australia
5 Department of Cell Biology, Duke University Medical Center, Durham, NC, USA; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA
6 Department of Medicine, Duke University Medical Center, Durham, NC, USA; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA
7 Department of Physiology, Medicine and Pediatrics, Queen's University, Kingston, Ontario, Canada
* To whom correspondence should be addressed. E-mail: Walke082{at}mc.duke.edu.
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 physiologic homeostasis. G protein-coupled receptor kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M2 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 M2 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 COPD.
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