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Background  The influx of extracellular Ca 2+  into mast cells is critical for the FcεR1-dependent release of preformed granule-derived mediators and newly synthesised autacoids and cytokines. The Orai(CRACM) ion channel family provide the major pathway through which this Ca 2+  influx occurs. However the individual role of each of the three members of the Orai channel family in Ca 2+  influx and mediator release has not been defined in human mast cells.    Objective  To assess whether there might be value in targeting individual Orai family members for the inhibition of FcεRI-dependent human lung mast cells (HLMC) mediator release.    Methods  We used an adenoviral delivery system to transduce HLMCs with shRNAs targeted against Orai1 and Orai2 or with cDNAs directing the expression of dominant-negative mutations of the three known Orai channels.    Results  shRNA-mediated knockdown of Orai1 resulted in a significant reduction of approximately 50% in Ca 2+  influx and in the release of β-hexosaminidase (a marker of degranulation) and newly synthesized LTC 4  in activated HLMCs. In contrast shRNA knockdown of Orai2 resulted in only marginal reductions of Ca 2+  influx, degranulation and LTC 4  release. Transduced dominant-negative mutants of Orai1, -2 and -3 markedly reduced Orai currents and completely inhibited HLMC degranulation suggesting that Orai channels form heteromultimers in HLMCs, and that Orai channels comprise the dominant Ca 2+  influx pathway following FceRI-dependent HLMC activation. Inhibition of Orai currents did not alter HLMC survival. In addition we observed a significant down-regulation of the level of CRACM3 mRNA transcripts together with a small increase in the level of CRACM1 and CRACM2 transcripts following a period of sustained HLMC activation.    Conclusion and Clinical Relevance  Orai1 plays an important role in Ca 2+  influx and mediator release from HLMCs. Strategies which target Orai1 will effectively inhibit FcεRI-dependent HLMC activation, but spare off-target inhibition of Orai2 in other cells and body systems.

The Contribution of Orai(CRACM)1 and Orai(CRACM)2 Channels in Store-Operated Ca2+ Entry and Mediator Release in Human Lung Mast Cells