Elevated lung G protein levels and muscarinic receptor affinity in a mouse model of airway hyperreactivity

S. H. Gavett, M. Wills-Karp

Research output: Contribution to journalArticlepeer-review

Abstract

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 β2-adrenergic and muscarinic cholinergic receptor properties and their coupling to guanine nucleotide binding proteins (G proteins) in peripheral lung membrane fractions from these strains. No significant differences were found between the strains with regard to β2-adrenergic or muscarinic receptor density or antagonist affinity. No strain difference was found in β2-adrenergic receptor affinity for isoproteronol in the presence or absence of the nonhydrolyzable guanine nucleotide 5'-guanylimidodiphosphate [Gpp(NH)p]. In contrast, affinity of the high-affinity carbachol binding site of muscarinic receptors was threefold greater in A/J lung 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 was 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(sα) and G(iα) proteins in peripheral lung were significantly greater in the A/J strain compared with the C3H/HeJ strain (40 and 20% greater, respectively). These studies suggest that airway hyperreactivity in A/J mice is not associated with alterations in β2-adrenoceptors, but may be a result of enhanced muscarinic receptor signal transduction due to increased agonist affinity for muscarinic receptors and upregulation of G protein levels.

Original languageEnglish (US)
Pages (from-to)L493-L500
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume265
Issue number5 9-5
DOIs
StatePublished - 1993

Keywords

  • asthma
  • guanine nucleotide
  • inbred strains
  • muscarinic receptor
  • β-adrenoceptor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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