Airway smooth muscle hypertrophy contributes to the narrowing of asthmatic airways. Activation of the mitogen-activated protein kinases is an important event in mediating cell proliferation. Because the monomeric G protein p21 ras is an important intermediate leading to activation of mitogen-activated protein kinases, we questioned which heterotrimeric G protein-coupled receptors were linked to the activation of p21 ras in cultured human airway smooth muscle and which of the heterotrimeric G protein subunits (α or βγ) transmitted the activation signal. Carbachol and endothelin-1 increased GTP-bound p21 ras in a pertussis toxin-sensitive manner [ratio of [32P]GTP to ([32P]GTP + [32P]GDP): control, 30 ± 1.7; 3 min of 1 μM carbachol, 39 ± 1.1; 3 min of 1 μM endothelin-1, 40 ± 1.2], whereas histamine, bradykinin, and KCl were without effect. Transfection of an inhibitor of the G protein βγ-subunit [the carboxy terminus (Gly495–Leu689) of the β-adrenoceptor kinase 1] failed to inhibit the carbachol-induced activation of p21 ras . These data suggest that Gi- but not Gq-coupled receptors activate p21 ras in human airway smooth muscle cells, and this effect most likely involves the α-subunit.
Arrestin Specificity for G Protein-coupled Receptors in Human Airway Smooth Muscle
