Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3

Citation
Jkl. Walker et al., Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3, AM J P-REG, 45(4), 1999, pp. R1214-R1221
Citations number
29
Categorie Soggetti
Physiology
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
ISSN journal
03636119 → ACNP
Volume
45
Issue
4
Year of publication
1999
Pages
R1214 - R1221
Database
ISI
SICI code
0363-6119(199904)45:4<R1214:AAACRI>2.0.ZU;2-3
Abstract
Contraction and relaxation of airway smooth muscles is mediated, in part, b y G protein-coupled receptors (GPCRs) and dysfunction of these receptors ha s been implicated in asthma. Phosphorylation of GPCRs, try G protein-couple d receptor kinase (GRK), is an important mechanism involved in the dampenin g of GPCR signaling. To determine whether this mechanism might play a role in airway smooth muscle physiology, we examined the airway pressure time in dex and heart rate (HR) responses to intravenous administration of the chol inergic agonist methacholine (MCh) in genetically altered mice lacking one copy of GRK2 (GRK2 +/-), homozygous GRK3 knockout (GRK3 -/-), and wild-type littermates. (GRK2 -/- mice die in utero.) GRK3 -/- mice demonstrated a si gnificant enhancement in the airway response to 100 and 250 mu g/kg doses o f MCh compared with wild-type and GRK2 +/- mice. GRK3 -/- mice also display ed an enhanced sensitivity of the airway smooth muscle response to MCh. In addition, GRK3 -/- mice displayed an altered HR recovery from MCh-induced b radycardia. Although direct stimulation of cardiac muscarinic receptors mea sured as vagal stimulation-induced bradycardia was similar in GRK3 -/- and wild-type mice, the baroreflex increase in HR associated with sodium nitrop russide-induced hypotension was significantly greater in GRK3 -/- than wild -type mice. Therefore, these data demonstrate that in the mouse, GRK3 may b e involved in modulating the cholinergic response of airway smooth muscle a nd in regulating the chronotropic component of the baroreceptor reflex.