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Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)–Orai1 Association in Human Platelets

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Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE).

Approach and Results—

SOCE is a major mechanism for calcium influx controlled by the intracellular Ca2+ stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood. Our results demonstrate that STIM1 interacts with FLNA on calcium store depletion in human platelets. The interaction is dependent on the phosphorylation of FLNA at Ser2152 by the cAMP-dependent protein kinase. Impairment of FLNA phosphorylation and knockdown of FLNA expression using siRNA increased SOCE in platelets. Similarly, SOCE was significantly greater in FLNA-deficient melanoma M2 cells than in the FLNA-expressing M2 subclone A7. Expression of FLNA in M2 cells attenuated SOCE, an effect prevented when the cells were transfected with the nonphosphorylatable FLNA S2152A mutant. Transfection of M2 cells with the STIM1(K684,685E) mutant reduced the STIM1–FLNA interaction. In platelets, attenuation of FLNA expression using siRNA resulted in enhanced association of STIM1 with the cytoskeleton, greater STIM1–Orai1 interaction, and SOCE. Introduction of an anti-FLNA (2597–2647) antibody attenuated the STIM1–FLNA interaction and enhanced thrombin-induced platelet aggregation.


Our results indicate that FLNA modulates SOCE and then the correct platelet function, by fine-tuning the distribution of STIM1 in the cytoskeleton and the interaction with Orai1 channels.
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Keywords: calcium signaling; filamins; ion channel; phosphorylation; stromal interaction molecule 1

Document Type: Research Article

Publication date: February 1, 2018

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