ELEVATED LUNG G-PROTEIN LEVELS AND MUSCARINIC RECEPTOR AFFINITY IN A MOUSE MODEL OF AIRWAY HYPERREACTIVITY

A genetic model of airway hyperreactivity has been described in which strains of mice are hyperresponsive (A/J) or hyporesponsive (C3H/HeJ) to intravenous acetylcholine challenge. To determine the mechanism of this differential responsiveness, we compared beta2-adrenergic and mus carinic cholinergic receptor properties and their coupling to guanine nucleotide binding proteins (G proteins) in peripheral lung membrane f ractions from these strains. No significant differences were found bet ween the strains with regard to beta2-adrenergic or muscarinic recepto r density or antagonist affinity. No strain difference was found in be ta2-adrenergic receptor affinity for isoproteronol in the presence or absence of the nonhydrolyzable guanine nucleotide 5'-guanylimidodiphos phate [Gpp(NH)p]. In contrast, affinity of the high-affinity carbachol binding site of muscarinic receptors was threefold greater in A/J lun g compared with C3H/HeJ lung (pK(H) = 7.34 +/- 0.16 vs. 6.79 +/- 0.06, respectively, P < 0.05). In the presence of Gpp(NH)p, this affinity w as decreased sevenfold in A/J lung but was not significantly affected in C3H/HeJ lung, suggesting that muscarinic receptors in A/J lung are more effectively coupled to G proteins. Levels of G(salpha) and G(ialp ha) proteins in peripheral lung were significantly greater in the A/J strain compared with the C3H/HeJ strain (40 and 20% greater, respectiv ely). These studies suggest that airway hyperreactivity in A/J mice is not associated with alterations in beta2-adrenoceptors, but may be a result of enhanced muscarinic receptor signal transduction due to incr eased agonist affinity for muscarinic receptors and upregulation of G protein levels.