Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor.
Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor.
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DOI：
10.1002/eji.200637024
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发表时间：
2007-06
影响因子：
5.4
通讯作者：
Bradding, Peter
中科院分区：
文献类型：
--
作者：
Duffy, S Mark;Cruse, Glenn;Brightling, Christopher E;Bradding, Peter
人肺肥大细胞（HLMC）表达Ca 2+激活的K+通道KCa 3.1，其在IgE依赖性激活后开放。这使细胞膜超极化并增强Ca 2+内流和脱粒。此外，阻断KCa 3.1可显著抑制HLMC向多种趋化刺激的迁移。β 2肾上腺素受体通过Gα s偶联机制减弱KCa 3.1的激活，而不依赖于cAMP。腺苷是一种重要的介质，分别通过Gα s偶联的A2 A和A2 B腺苷受体减弱和增强HLMC介质释放。我们发现，在抑制HLMC脱粒的浓度（10-5-10-3 M），腺苷关闭KCa 3.1的剂量依赖性和可逆性。腺苷对KCa 3.1的抑制作用可被选择性腺苷A2 A受体拮抗剂ZM 241385部分逆转，但不能被A2 B受体拮抗剂MRS 1754逆转，腺苷的作用可被选择性A2 A受体激动剂CGS 21680模拟。腺苷还打开了非选择性阳离子携带的去极化电流。正如KCa 3.1在HLMC迁移中的作用所预测的那样，腺苷消除了HLMC对哮喘气道平滑肌条件培养基的趋化性。总之，Gα s偶联腺苷A2 A受体关闭KCa 3.1，提供了腺苷抑制HLMC迁移和脱粒的明确机制。具有通道调节功能的A2 A受体激动剂可用于治疗肥大细胞介导的疾病。
Human lung mast cells (HLMC) express the Ca2+-activated K+ channel KCa3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca2+ influx and degranulation. In addition, blockade of KCa3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the β2adrenoceptor through a Gαs-coupled mechanism independent of cyclic AMP. Adenosine is an important mediator that both attenuates and enhances HLMC mediator release through the Gαs-coupled A2A and A2B adenosine receptors, respectively. We show that at concentrations that inhibit HLMC degranulation (10–5–10–3 M), adenosine closes KCa3.1 both dose-dependently and reversibly. KCa3.1 suppression by adenosine was reversed partially by the selective adenosine A2A receptor antagonist ZM241385 but not by the A2B receptor antagonist MRS1754, and the effects of adenosine were mimicked by the selective A2A receptor agonist CGS21680. Adenosine also opened a depolarising current carried by non-selective cations. As predicted from the role of KCa3.1 in HLMC migration, adenosine abolished HLMC chemotaxis to asthmatic airway smooth muscle-conditioned medium. In summary, the Gαs-coupled adenosine A2A receptor closes KCa3.1, providing a clearly defined mechanism by which adenosine inhibits HLMC migration and degranulation. A2A receptor agonists with channel-modulating function may be useful for the treatment of mast cell-mediated disease.