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|Title:||CRACM/Orai ion channel expression and function in human lung mast cells|
Duffy, S. Mark
Leyland, Mark L.
Morrison, Valerie S.
|Publisher:||Elsevier for the American Academy of Allergy, Asthma and Immunology|
|Citation:||Journal of Allergy and Clinical Immunology, 2012, 129 (6), pp. 1628–1635.e2|
|Abstract:||Background: Influx of extracellular Ca[superscript 2+] 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 Ca[superscript 2+] influx is unknown. The recently discovered members of the CRACM/Orai ion channel family that carries the Ca[superscript 2+] release–activated Ca[superscript 2+] current are candidates. Objectives: To investigate the expression and function of CRACM channels in HLMCs. Methods: CRACM mRNA, protein, and functional expression were examined in purified HLMCs and isolated human bronchus. Results: 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 Ca[superscript 2+]-selective current obtained under both conditions was blocked by 10 μM La[superscript 3+] and Gd[superscript 3+], known blockers of CRACM channels, and 2 distinct and specific CRACM-channel blockers—GSK-7975A and Synta-66. Both blockers reduced FcεRI-dependent Ca[superscript 2+] influx, and 3 μM GSK-7975A and Synta-66 reduced the release of histamine, leukotriene C[subscript 4], 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. Conclusions: The presence of CRACM channels, a CRACM-like current, and functional inhibition of HLMC Ca[superscript 2+] 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.|
|Description:||Full text of this item is not currently available on the LRA. The final published version may be available through the links above.|
|Appears in Collections:||Published Articles, Dept. of Biochemistry|
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