Store-Operated Calcium Entry (SOCE) is a ubiquitous Ca2+ influx mechanism first described
in 1986 (Putney, 1986). This conserved mechanism results from the interaction between the
tetraspanning ORAI1 channel located in plasma membrane and the unique endoplasmic reticulum
(ER) Ca2+ sensor, stromal interaction molecule 1 (STIM1), via their respective intracellular
domains (Roos et al., 2005; Csutora et al., 2008). Moreover, there are two homologs of ORAI1,
namely ORAI2 and ORAI3, all generating SOCE with the same mechanism

Agnese Secondo

Francisco Javier Martin-Romero

Joanna Gruszczynska-Biegala

Tarik Smani

Frontiers in Cellular Neuroscience

English

Directory of Open Access Journals

Editorial: Molecular Components of Store-Operated Calcium Entry in Health and Disease

Gruszczynska-Biegala, Joanna

Martin-Romero, Francisco Javier

Smani, Tarik

Secondo, Agnese

IRIS UniversitÃ  Politecnica delle Marche

Archivio della ricerca - Università degli studi di Napoli Federico II

EDITORIALpublished: 05 October 2021doi: 10.3389/fncel.2021.771138Frontiers in Cellular Neuroscience | www.frontiersin.org 1 October 2021 | Volume 15 | Article 771138Approved by:Dirk M. Hermann,University ofDuisburg-Essen, Germany*Correspondence:Joanna Gruszczynska-Biegalajgruszczynska@imdik.pan.pl†These authors have contributedequally to this workSpecialty section:This article was submitted toCellular Neuropathology,a section of the journalFrontiers in Cellular NeuroscienceReceived: 05 September 2021Accepted: 15 September 2021Published: 05 October 2021Citation:Gruszczynska-Biegala J,Martin-Romero FJ, Smani T andSecondo A (2021) Editorial: MolecularComponents of Store-OperatedCalcium Entry in Health and Disease.Front. Cell. Neurosci. 15:771138.doi: 10.3389/fncel.2021.771138Editorial: Molecular Components ofStore-Operated Calcium Entry inHealth and DiseaseJoanna Gruszczynska-Biegala 1*†, Francisco Javier Martin-Romero 2†, Tarik Smani 3,4† andAgnese Secondo 5†1 Laboratory of Molecular Biology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland,2 Institute of Molecular Pathology Biomarkers, University of Extremadura, Badajoz, Spain, 3Group of CardiovascularPathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, Seville,Spain, 4Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain, 5Department ofNeuroscience, “Federico II” University of Naples, Naples, ItalyKeywords: SOCE, STIM1, STIM2, TRP channels, ORAIEditorial on the Research TopicMolecular Components of Store-Operated Calcium Entry in Health and DiseaseStore-Operated Calcium Entry (SOCE) is a ubiquitous Ca2+ influx mechanism first describedin 1986 (Putney, 1986). This conserved mechanism results from the interaction between thetetraspanning ORAI1 channel located in plasma membrane and the unique endoplasmic reticulum(ER) Ca2+ sensor, stromal interaction molecule 1 (STIM1), via their respective intracellulardomains (Roos et al., 2005; Csutora et al., 2008). Moreover, there are two homologs of ORAI1,namely ORAI2 and ORAI3, all generating SOCE with the same mechanism.Molecularly, upon ER Ca2+ depletion, STIM1 senses the filling state of ER with its N-terminus characterized by a low affinity for Ca2+ ion (200 nM-600microM). After dimerization,STIM1 diffuses to the plasma membrane regions where it interacts with ORAI1 inducing SOCEthrough Calcium Release-Activated Calcium (CRAC) channel opening. This event may mediate alocalized increase in the intracellular Ca2+ concentration useful to recharge ER of Ca2+ contentby sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) intervention. Besides STIM1, also STIM2may induce activation of ORAI1 (Brandman et al., 2007) but with a weak Ca2+ entry that isnevertheless able to trigger NFAT1 activation (Son et al., 2020).Accumulated evidence suggests that SOCE dysfunction may produce Ca2+ dyshomeostasisin both excitable and non-excitable cells, thus participating to the pathogenesis of a largespectrum of diseases most of which are due to the modification of ORAI1/STIM1 interactionin consequence of changes in their expression or following a disruption of SOCE machinery.However, genetic modification of the two major players could also occur. For instance, loss offunction mutations of ORAI1 and STIM1/STIM2 abolishes SOCE, thus causing autoimmunityand severe combined immunodeficiency (SCID)-like diseases. In contrast, autosomal dominantgain-of–function mutations in ORAI1 and STIM1 determine a sustained increase in CRAC andSOCE causing a large spectrum of diseases like Stormorken syndrome and nonsyndromic tubularaggregate myopathy (TAM) (Lacruz and Feske, 2015). In this respect the study by Conte et al. showssome of the adaptive or compensatory mechanisms able to counteract the genetic-encoded Ca2+dyshomeostasis and describes the alteration in the differentiation process of muscle cells derivingfrom TAM-patients carrying STIM1 L96V mutation.Mechanistically, mutations in the transmembrane domains of the pore region of ORAI channelsmay produce SOCE alterations. Of note, the elucidation of the isoform-specific mutations mayGruszczynska-Biegala et al. Editorial: SOCE Components in Health and Diseaseprovide useful targets for selective drug development. In thiscontext, the study by Tiffner et al. shows the molecularconsequences of the enhanced hydrophobicity along TM3 ofORAI1 or ORAI3 structure on the gain-of-function of SOCE andCRAC currents.In this Research Topic, two manuscripts review the roleof ORAI1 in cardiovascular remodeling and heart failure. Thefirst article by Luo et al. provides an overview of the newrole of ORAI1-mediated SOCE in the maladaptive cardiachypertrophy and heart failure. The review discusses the currentknowledge regarding the involvement of ORAI1 in hypertrophicdevelopment induced by neurohormonal stimulation in vitro orin vivo, using transgenic mice subjected to different proceduresthat induce cardiac hypertrophy and consequently heart failure.The other review article by Shawer et al. provides a broadperspective of the role ORAI1-mediated vascular smooth musclecell (VSMC) switching from contractile to synthetic phenotypes,a critical step for their proliferation and migration. Authorsfocus on the involvement of ORAI1 in the pathological vascularremodeling related to atherosclerosis, neointimal hyperplasia andrestenosis. They also discuss the potential mode of action of alarge list of SOCE inhibitors examined in different cell lines.Both reviews consider that new pharmacological selectiveinhibitors are valuable tools to study the role of SOCE in healthand disease, which might pave the way for the development oftherapeutic ORAI1 inhibitors to mitigate pathologic cardiac andvascular remodeling.Galeano-Otero et al. in an original article related to thecirculatory system highlight for the first time the role ofSARAF, SOCE-associated regulatory factor, in the activation ofendothelial cells and angiogenesis. The study nicely demonstratesthat SOCE participates in several steps of angiogenesis, such asendothelial cell proliferation and migration, tube formation, andsprouting, and shows that SARAF co-localizes and interacts withORAI1, which might sustain an enhanced Ca2+ entry in thesehighly proliferative cells during angiogenesis.Since the discovery of the molecular components of SOCE,including the STIM, ORAI and TRP proteins, a growingnumber of publications describe their functions in the healthyand diseased central nervous system (CNS) (Serwach andGruszczynska-Biegala, 2019). In this regard, Zhang and Husummarize the current literature reporting on the variableexpression of STIM, ORAI and TRPC in neurons andglial cells from different parts of the CNS. The authorsalso provide a systematic overview describing the currentunderstanding of the physiological and pathological roleof SOCE and its molecular components in each of thesebrain regions. The impact of existing therapies on SOCE isalso reviewed.Two additional review articles describe the relationshipbetween Huntington’s disease (HD) and SOCE (Latoszekand Czeredys). As an inherited neurodegenerative disorder,HD is characterized by the loss of γ-aminobutyric acid(GABA)-ergic medium spiny neurons (MSNs) in the striatum(Vonsattel and DiFiglia, 1998), and SOCE has been shownto be elevated in several HD models. Czeredys’s reviewprovides a comprehensive update on the implications of SOCE,STIM2, ORAIs and TRPCs in HD pathology using variousHD models, including YAC128 mice (HD transgenic model),HD cellular models, and induced pluripotent stem cell-basedGABAergic MSNs that are obtained from fibroblasts of adult HDpatients. The author further discusses potential drug candidatesthat may restore normal SOCE and consequently preventdendritic spine loss in HD. Latoszek and Czeredys reviewrecent data indicating that HD is also a neurodevelopmentaldisease, as neuronal cells differentiated from juvenile HDpatient-derived iPSCs show deficits in development and adultneurogenesis. Finally, the authors also review different protocolsto obtain MSNs and brain organoids as powerful tools tostudy HD.Also related to HD, Vigont et al. in an original article,demonstrate the role of STIM2 in the elevated Ca2+ entryin HD cellular models. More specifically, these authorsgenerated MSNs modeling a juvenile form of HD andshow high levels of SOCE using patch-clamp. Upregulationof STIM2 protein expression was also observed, and theshRNA-mediated suppression of STIM2 expression attenuatedSOCE. For this reason, Vigont et al. used the anti-HDdrug EVP4593 to demonstrate that this drug decreasedhuntingtin expression and also the expression of STIM2,postulating that STIM2 could be a novel therapeutic targetfor HD.In addition to the main components of SOCE, beingthe STIM and ORAI proteins, an increasing number ofproteins have been also reported to play an important rolein the STIM-ORAI dependent regulation of SOCE. Serwachand Gruszczynska-Biegala thoroughly review and summarizethe current knowledge about STIM protein target molecules,including positive (mGluR, septins, synaptopodin, POST, EB andGolli proteins) and negative (Homer, SARAF, presenilin1, andNEUROD2) regulators and effectors [L-type voltage-operatedCa2+ channels (VOCCs) and receptors such as AMPAR andNMDAR] in the CNS. This review also highlights the importanceof the interaction of STIM proteins with their target proteins inpathology, such as hypoxic/ischemic neuronal injury, epilepsy,Alzheimer’s, Huntington’s and Parkinson’s diseases, and inphysiological conditions of the CNS.Finally, in this issue Coronas et al. review the role of Ca2+channels in neural stem cells (NSCs) and glioblastoma stem cells(GSCs), derived from oncogenic mutations in adult NSCs andresponsible for the emergence of malignant brain tumors. Thereview focuses on the Ca2+ toolkit and its physiological rolein GSCs, in NSCs and their progenies to show that stemnessis controlled by VOCCs, store-operated Ca2+ channels (SOCs),IP3Rs in NSCs, and by VOCCs, nicotinic receptors and TRPVsin GSCs.In summary, this special issue of Frontiers in CellularNeuroscience provides a comprehensive overview of the mostrecent data on the role of SOCE and related proteins: STIMs,ORAIs and others that regulate them, in the physiology andpathology of a variety of cells. It highlights the importance ofSOCE and its regulatory proteins as potential drug targets forfuture therapies against neurodegenerative, cardiovascular ormuscular diseases and brain tumors.Frontiers in Cellular Neuroscience | www.frontiersin.org 2 October 2021 | Volume 15 | Article 771138Gruszczynska-Biegala et al. Editorial: SOCE Components in Health and DiseaseAUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.FUNDINGJG-B was supported by the National Science Centre grant(research project no. 2017/26/E/NZ3/01144), FJM-R wassupported by the Spanish Ministry of Science and Innovation(research project BFU2017-82716-P), TS was supported by theSpanish Ministry of Science and Innovation (research projectno. PID2019-104084GB-C22/ AEI/10.13039/501100011033),AS was supported by PRIN2015–Prot. 2015KRYSJN (ItalianMinistry of Education and Research), Progetto Speciale diAteneo CA.04_CDA_n_103 27.03.2019 and Progetto di AteneoLinea A CdA_54_2020_FRA.ACKNOWLEDGMENTSEditors thank deeply all the authors for their scientificcontributions and the reviewers for their support andconstructive criticism in refining the manuscripts in thisResearch Topic.REFERENCESBrandman, O., Liou, J., Park, W. S., and Meyer, T. (2007). STIM2 is a feedbackregulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels.Cell 131, 1327–1339. doi: 10.1016/j.cell.2007.11.039Csutora, P., Peter, K., Kilic, H., Park, K. M., Zarayskiy, V., Gwozdz, T., et al. (2008).Novel role for STIM1 as a trigger for calcium influx factor production. J. Biol.Chem. 283, 14524–14531. doi: 10.1074/jbc.M709575200Lacruz, R. S., and Feske, S. (2015). Diseases caused by mutations in ORAI1 andSTIM1. Ann. N. Y. Acad. Sci. 1356, 45–79. doi: 10.1111/nyas.12938Putney, J. W. Jr. (1986). A model for receptor-regulated calcium entry. CellCalcium 7, 1–12. doi: 10.1016/0143-41608690026-6Roos, J., DiGregorio, P. J., Yeromin, A. V., Ohlsen, K., Lioudyno, M., Zhang, S.,et al. (2005). STIM1, an essential and conserved component of store-operatedCa2+ channel function. J. Cell Biol. 169, 435–445. doi: 10.1083/jcb.200502019Serwach, K., and Gruszczynska-Biegala, J. (2019). STIM proteins and glutamatereceptors in neurons: role in neuronal physiology and neurodegenerativediseases. Int. J. Mol. Sci. 20:2289. doi: 10.3390/ijms20092289Son, G. Y., Subedi, K. P., Ong, H. L., Noyer, L., Saadi, H., Zheng, C., et al. (2020).STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and conferscoupling of Ca2+ entry with NFAT1 activation. Proc. Natl. Acad. Sci.U.S.A. 117,16638–16648. doi: 10.1073/pnas.1915386117Vonsattel, J. P., and DiFiglia, M. (1998). Huntington disease. J. Neuropathol.Exp. Neurol. 57, 369–384. doi: 10.1097/00005072-199805000-00001Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Gruszczynska-Biegala, Martin-Romero, Smani and Secondo. Thisis an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which does notcomply with these terms.Frontiers in Cellular Neuroscience | www.frontiersin.org 3 October 2021 | Volume 15 | Article 771138

Martín-Romero, Francisco Javier

Smani Hajami, Tarik

idUS. Depósito de Investigación Universidad de Sevilla

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Editorial: Molecular Components of Store-Operated Calcium Entry in Health and Disease

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