Sh. Gavett et M. Willskarp, ELEVATED LUNG G-PROTEIN LEVELS AND MUSCARINIC RECEPTOR AFFINITY IN A MOUSE MODEL OF AIRWAY HYPERREACTIVITY, The American journal of physiology, 265(5), 1993, pp. 120000493-120000500
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.