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β 2 ‐Adrenoceptor regulation of the K + channel iK Ca 1 in human mast cells
Author(s) -
Mark Duffy S.,
Cruse Glenn,
Lawley Wendy J.,
Bradding Peter
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3439fje
Subject(s) - salbutamol , mast cell , chemistry , agonist , intracellular , gating , receptor , hyperpolarization (physics) , degranulation , antagonist , medicine , endocrinology , biophysics , microbiology and biotechnology , biology , biochemistry , immunology , asthma , stereochemistry , nuclear magnetic resonance spectroscopy
Human mast cells express the intermediate conductance Ca 2+ ‐activated K + channel iKCa1, which opens following IgE‐dependent activation. This results in cell membrane hyperpolarization and potentiation of both Ca 2+ influx and degranulation. Mast cell activation is attenuated following exposure to β 2 ‐adrenoceptor agonists such as salbutamol, an effect postulated to operate via intracellular cyclic AMP. In this study, we show that salbutamol closes iK Ca 1 in mast cells derived from human lung and peripheral blood. Salbutamol (1–10 µM) inhibited iK Ca 1 currents following activation with both anti‐IgE and the iK Ca 1 opener 1‐EBIO, and was reversed by removing salbutamol or by the addition of the selective β 2 ‐adrenoceptor antagonist and inverse agonist ICI 118551. Interestingly, ICI 118551 consistently opened iK Ca 1 in quiescent cells, suggesting that constitutive β2‐receptor signaling suppresses channel activity. Manipulation of intracellular cAMP, Gαi, and Gαs demonstrates that the β 2 ‐adrenergic effects are consistent with a membrane‐delimited mechanism involving Gαs. This is the first demonstration that gating of the iK Ca 1 channel is regulated by a G protein‐coupled receptor and provides a clearly defined mechanism for the mast cell “stabilizing” effect of β 2 ‐agonists. Furthermore, the degree of constitutive β 2 ‐receptor “tone” may control the threshold for human mast cell activation through the regulation of iK Ca 1.