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 ( or ) 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 -subunit [the carboxy terminus (Gly⁴⁹⁵-Leu⁶⁸⁹) of the -adrenoceptor kinase 1] failed to inhibit the carbachol-induced activation of p21^ras. These data suggest that G_i- but not G_q-coupled receptors activate p21^ras in human airway smooth muscle cells, and this effect most likely involves the -subunit.

G proteins; carbachol; endothelin; epidermal growth factor; bradykinin; histamine; pertussis toxin

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