Engagement of the EP2 prostanoid receptor closes the K+ channel KCa3.1 in human lung mast cells and attenuates their migration.
Engagement of the EP2 prostanoid receptor closes the K+ channel KCa3.1 in human lung mast cells and attenuates their migration.
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DOI：
10.1002/eji.200738106
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发表时间：
2008-09
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;Cockerill, Sarah L.;Brightling, Chris E.;Bradding, Peter
人肺肥大细胞（HLMC）表达钙激活的钾通道KCa 3.1，它在其迁移到各种不同的趋化刺激中起着至关重要的作用。β2-肾上腺素受体和腺苷A2 A受体通过不依赖于环AMP的Gs偶联机制减弱KCa 3.1激活。前列腺素E2通过Gi偶联的EP 3前列腺素受体促进小鼠骨髓来源的肥大细胞的脱粒和迁移，并诱导人脐带血来源的肥大细胞分泌LTC 4和细胞因子。然而，PGE 2结合到HLMC上的GS偶联EP 2受体抑制其脱颗粒。我们发现，EP 2受体参与关闭HLMC中的KCa 3.1。在这方面，EP 2受体特异性激动剂布他前列素比PGE 2更有效，两种激动剂的作用均被EP 2受体拮抗剂AH 6809逆转。布他前列素显著抑制富含趋化因子的气道平滑肌条件培养基诱导的HLMC迁移。有趣的是，单独的PGE 2在高浓度（1 µM）下对HLMC具有趋化性，但在EP 2受体阻断后对HLMC是更有效的化学引诱剂。因此，Gs偶联的EP 2受体关闭HLMC中的KCa 3.1，并减弱趋化因子和PGE 2依赖性HLMC迁移。具有KCa 3.1调节功能的EP 2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 plays a crucial role in their migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the β2-adrenoceptor and the adenosine A2A receptor through a Gs-coupled mechanism independent of cyclic AMP. Prostaglandin E2 promotes degranulation and migration of mouse bone marrow-derived mast cells through the Gi-coupled EP3 prostanoid receptor, and induces LTC4 and cytokine secretion from human cord blood-derived mast cells. However, PGE2 binding to the Gs-coupled EP2 receptor on HLMC inhibits their degranulation. We show that EP2 receptor engagement closes KCa3.1 in HLMC. The EP2 receptor-specific agonist butaprost was more potent than PGE2 in this respect, and the effects of both agonists were reversed by the EP2 receptor antagonist AH6809. Butaprost markedly inhibited HLMC migration induced by chemokine-rich airway smooth muscle-conditioned media. Interestingly, PGE2 alone was chemotactic for HLMC at high concentrations (1 µM), but was a more potent chemoattractant for HLMC following EP2 receptor blockade. Therefore, the Gs-coupled EP2 receptor closes KCa3.1 in HLMC and attenuates both chemokine- and PGE2-dependent HLMC migration. EP2 receptor agonists with KCa3.1 modulating function may be useful for the treatment of mast cell-mediated disease.
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DOI：
10.1165/ajrcmb.10.5.8179909
发表时间：
1994-05-01
影响因子：
6.4
作者：
BRADDING, P;ROBERTS, JA;HOLGATE, ST
通讯作者：
HOLGATE, ST
影响因子：
14.2
作者：
Duffy, SM;Lawley, WJ;Bradding, P
通讯作者：
Bradding, P
影响因子：
5.4
作者：
Duffy, S Mark;Cruse, Glenn;Brightling, Christopher E;Bradding, Peter
通讯作者：
Bradding, Peter
DOI：
10.1073/pnas.89.22.11051
发表时间：
1992-11-15
影响因子：
11.1
作者：
KUME, H;GRAZIANO, MP;KOTLIKOFF, MI
通讯作者：
KOTLIKOFF, MI
影响因子：
158.5
作者：
Brightling, CE;Bradding, P;Pavord, ID
通讯作者：
Pavord, ID