Reference : The M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussi...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
The M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussis toxin-sensitive G proteins
Chahdi, A. [> >]
Daeffler, L. [> >]
Bueb, Jean-Luc mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Gies, J. P. [> >]
Landry, Y. [> >]
Naunyn-Schmiedeberg's Archives of Pharmacology
Springer Science & Business Media B.V.
Yes (verified by ORBilu)
New York
[en] drug effects ; Diamines ; GTP-Binding Proteins ; Histamine Release ; Inositol Phosphates ; Male ; Mast Cells ; N-Acetylneuraminic Acid ; Neuraminidase ; Pertussis Toxin ; Rats ; Rats, Wistar ; Signal Transduction ; Virulence Factors, Bordetella ; metabolism ; pharmacology ; physiology ; Animals
[en] Methoctramine, a selective M2 muscarinic cholinergic receptor antagonist, has been reported to activate phosphoinositide breakdown at high concentrations. Its polyamine structure suggests a putative activation of guanine nucleotide-binding proteins (G proteins). Incubation of methoctramine with rat peritoneal mast cells resulted in a dose-dependent noncytotoxic histamine release, with an EC50 of 20 microM and a maximum effect at 1 mM. Atropine, pirenzepine and HHSiD neither inhibited methoctramine-induced histamine release nor stimulated histamine release. Histamine release and inositol phosphates generation induced by methoctramine were both inhibited by pertussis toxin pretreatment. Benzalkonium chloride, a selective inhibitor of histamine secretion induced by basic secretagogues, inhibited the secretory response to methoctramine. [p-Glu5, D-Trp7,9,l0]-SPs5-11 (GPAnt-2), a well-characterized antagonist of G proteins, blocked the methoctramine-induced histamine release when the antagonist was allowed to reach its intracellular target by streptolysin O-permeabilization. The response to methoctramine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase. The response of mast cells was restored by permeabilization of the plasma membrane. These results demonstrate that methoctramine, following its entry into the cell and the involvement of pertussis toxin-sensitive G proteins, activates phosphoinositide hydrolysis leading to mast cell exocytosis.

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