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Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets.
Arterioscler Thromb Vasc Biol 2018; 38(2):386-397AT

Abstract

OBJECTIVE

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.

CONCLUSIONS

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.

Authors+Show Affiliations

From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.).From the Department of Physiology, University of Extremadura, Cáceres, Spain (J.J.L., L.A., I.J., J.S.-C., P.C.R., J.A.R.); Department of Hematology, Hospital San Pedro de Alcantara, Cáceres, Spain (N.B.); INSERM Unité Mixte de Recherche-Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (R.B.); and Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Spain (T.S.). jarosado@unex.es.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29284605

Citation

Lopez, Jose J., et al. "Filamin a Modulates Store-Operated Ca2+ Entry By Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 38, no. 2, 2018, pp. 386-397.
Lopez JJ, Albarrán L, Jardín I, et al. Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets. Arterioscler Thromb Vasc Biol. 2018;38(2):386-397.
Lopez, J. J., Albarrán, L., Jardín, I., Sanchez-Collado, J., Redondo, P. C., Bermejo, N., ... Rosado, J. A. (2018). Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(2), pp. 386-397. doi:10.1161/ATVBAHA.117.310139.
Lopez JJ, et al. Filamin a Modulates Store-Operated Ca2+ Entry By Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets. Arterioscler Thromb Vasc Biol. 2018;38(2):386-397. PubMed PMID: 29284605.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets. AU - Lopez,Jose J, AU - Albarrán,Letizia, AU - Jardín,Isaac, AU - Sanchez-Collado,Jose, AU - Redondo,Pedro C, AU - Bermejo,Nuria, AU - Bobe,Regis, AU - Smani,Tarik, AU - Rosado,Juan A, Y1 - 2017/12/28/ PY - 2017/08/19/received PY - 2017/12/13/accepted PY - 2017/12/30/pubmed PY - 2019/1/15/medline PY - 2017/12/30/entrez KW - calcium signaling KW - filamins KW - ion channel KW - phosphorylation KW - stromal interaction molecule 1 SP - 386 EP - 397 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 38 IS - 2 N2 - OBJECTIVE: 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. CONCLUSIONS: 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/29284605/Filamin_A_Modulates_Store_Operated_Ca2+_Entry_by_Regulating_STIM1__Stromal_Interaction_Molecule_1__Orai1_Association_in_Human_Platelets_ L2 - http://www.ahajournals.org/doi/full/10.1161/ATVBAHA.117.310139?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -