Adenosine closes the K(+) channel K(Ca)3.1 in human lung mast cells and inhibits their migration via the adenosine A(2A) receptor

Human lung mast cells (HLMC) express the Ca(2+)-activated K(+) channel K(Ca)3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca(2+) influx and degranulation. In addition, blockade of K(Ca)3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. K(Ca)3.1 activation is attenuated by the β(2)adrenoceptor through a G(αs)-coupled mechanism independent of cyclic AMP. Adenosine is an important mediator that both attenuates and enhances HLMC mediator release through the G(αs)-coupled A(2A) and A(2B) adenosine receptors, respectively. We show that at concentrations that inhibit HLMC degranulation (10(–5)–10(–3) M), adenosine closes K(Ca)3.1 both dose-dependently and reversibly. K(Ca)3.1 suppression by adenosine was reversed partially by the selective adenosine A(2A) receptor antagonist ZM241385 but not by the A(2B) receptor antagonist MRS1754, and the effects of adenosine were mimicked by the selective A(2A) receptor agonist CGS21680. Adenosine also opened a depolarising current carried by non-selective cations. As predicted from the role of K(Ca)3.1 in HLMC migration, adenosine abolished HLMC chemotaxis to asthmatic airway smooth muscle-conditioned medium. In summary, the G(αs)-coupled adenosine A(2A) receptor closes K(Ca)3.1, providing a clearly defined mechanism by which adenosine inhibits HLMC migration and degranulation. A(2A) receptor agonists with channel-modulating function may be useful for the treatment of mast cell-mediated disease.