CRACM/Orai ion channel expression and function in human lung mast cells.
CRACM/Orai ion channel expression and function in human lung mast cells.
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DOI：
10.1016/j.jaci.2012.01.070
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发表时间：
2012-06
影响因子：
14.2
通讯作者：
Bradding, Peter
中科院分区：
文献类型：
--
作者：
Ashmole, Ian;Duffy, S. Mark;Leyland, Mark L.;Morrison, Valerie S.;Begg, Malcolm;Bradding, Peter
细胞外Ca2+内流进入人肺肥大细胞（HLMCs）对于预先形成的颗粒衍生介质和新合成的类细胞因子和细胞因子的fc - ri依赖性释放是必不可少的。然而，这种Ca2+内流背后的离子通道的身份是未知的。最近发现的携带Ca2+释放激活的Ca2+电流的CRACM/Orai离子通道家族成员是候选者。目的：探讨CRACM通道在hlmc中的表达及功能。在纯化的hlmc和离体人支气管中检测CRACM mRNA、蛋白和功能表达。在hlmc中检测到CRACM1、-2和-3 mRNA转录物以及CRACM1和-2蛋白。在fcε ri依赖的HLMC激活后以及在30 μM三磷酸肌醇透析的HLMC中检测到cracm样电流。在这两种条件下获得的Ca2+选择电流被10 μM La3+和Gd3+阻断，这是已知的CRACM通道阻断剂，以及2种不同的特异性CRACM通道阻断剂gsk - 7975a和Synta-66阻断。两种阻滞剂均可减少fc - ri依赖性Ca2+内流，3 μM GSK-7975A和Synta-66可减少组胺、白三烯C4和细胞因子（IL-5/-8/-13和TNFα）的释放高达50%。Synta-66在离体组织中也能抑制过敏原依赖性支气管平滑肌收缩。CRACM通道的存在，CRACM样电流，以及CRACM通道阻滞剂对HLMC Ca2+内流、介质释放和过敏原诱导的支气管平滑肌收缩的功能抑制，支持了CRACM通道在fcε ri依赖性HLMC分泌中的作用。因此，CRACM通道是治疗哮喘和相关过敏性疾病的潜在治疗靶点。
Influx of extracellular Ca2+ into human lung mast cells (HLMCs) is essential for the FcεRI-dependent release of preformed granule-derived mediators and newly synthesized autacoids and cytokines. However, the identity of the ion channels underlying this Ca2+ influx is unknown. The recently discovered members of the CRACM/Orai ion channel family that carries the Ca2+ release–activated Ca2+ current are candidates. To investigate the expression and function of CRACM channels in HLMCs. CRACM mRNA, protein, and functional expression were examined in purified HLMCs and isolated human bronchus. CRACM1, -2, and -3 mRNA transcripts and CRACM1 and -2 proteins were detectable in HLMCs. A CRACM-like current was detected following FcεRI-dependent HLMC activation and also in HLMCs dialyzed with 30 μM inositol triphosphate. The Ca2+-selective current obtained under both conditions was blocked by 10 μM La3+ and Gd3+, known blockers of CRACM channels, and 2 distinct and specific CRACM-channel blockers—GSK-7975A and Synta-66. Both blockers reduced FcεRI-dependent Ca2+ influx, and 3 μM GSK-7975A and Synta-66 reduced the release of histamine, leukotriene C4, and cytokines (IL-5/-8/-13 and TNFα) by up to 50%. Synta-66 also inhibited allergen-dependent bronchial smooth muscle contraction in ex vivo tissue. The presence of CRACM channels, a CRACM-like current, and functional inhibition of HLMC Ca2+ influx, mediator release, and allergen-induced bronchial smooth muscle contraction by CRACM-channel blockers supports a role for CRACM channels in FcεRI-dependent HLMC secretion. CRACM channels are therefore a potential therapeutic target in the treatment of asthma and related allergic diseases.
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影响因子：
14.2
作者：
Duffy, SM;Lawley, WJ;Bradding, P
通讯作者：
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