Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor

Abstract

Human lung mast cells (HLMC) express the Ca²⁺-activated K⁺ channel K_Ca3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca²⁺ influx and degranulation. In addition, blockade of K_Ca3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. K_Ca3.1 activation is attenuated by the β₂adrenoceptor 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_Ca3.1 both dose-dependently and reversibly. K_Ca3.1 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_Ca3.1 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_Ca3.1, 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.