Orai1 inhibitor STIM2β regulates myogenesis by controlling SOCE dependent transcriptional factors

Kim, Kyu Min; Rana, Anshul; Park, Chan Young

doi:10.1038/s41598-019-47259-5

Cited by 12 publications

(10 citation statements)

References 45 publications

(38 reference statements)

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“…Additionally, involvement of STIM2.1 in myogenesis through the control of cell cycle arrest has been reported. The latter is achieved by STIM2.1-mediated inhibition of SOCE blocking the promotion of cell proliferation, which transitions cell fate from proliferation to differentiation [109].…”

Section: Stim22 Isoformsmentioning

confidence: 99%

STIM Proteins: An Ever-Expanding Family

Grabmayr

Romanin

Fahrner

2020

IJMS

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Stromal interaction molecules (STIM) are a distinct class of ubiquitously expressed single-pass transmembrane proteins in the endoplasmic reticulum (ER) membrane. Together with Orai ion channels in the plasma membrane (PM), they form the molecular basis of the calcium release-activated calcium (CRAC) channel. An intracellular signaling pathway known as store-operated calcium entry (SOCE) is critically dependent on the CRAC channel. The SOCE pathway is activated by the ligand-induced depletion of the ER calcium store. STIM proteins, acting as calcium sensors, subsequently sense this depletion and activate Orai ion channels via direct physical interaction to allow the influx of calcium ions for store refilling and downstream signaling processes. This review article is dedicated to the latest advances in the field of STIM proteins. New results of ongoing investigations based on the recently published functional data as well as structural data from nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations are reported and complemented with a discussion of the latest developments in the research of STIM protein isoforms and their differential functions in regulating SOCE.

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Section: Stim22 Isoformsmentioning

confidence: 99%

STIM Proteins: An Ever-Expanding Family

Grabmayr

Romanin

Fahrner

2020

IJMS

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“…[ 213 , 214 ]. Interestingly, the expression of this splice form increased in differentiating myotubes [ 213 , 215 ]. The KO of STIM2.1 in C2C12 muscle cells showed a decreased differentiation process, as highlighted by a reduced expression of myosin heavy chain and myogenin [ 215 ].…”

Section: Variety Of Stim Molecules Expressed In Adult Tissuementioning

confidence: 99%

“…Interestingly, the expression of this splice form increased in differentiating myotubes [ 213 , 215 ]. The KO of STIM2.1 in C2C12 muscle cells showed a decreased differentiation process, as highlighted by a reduced expression of myosin heavy chain and myogenin [ 215 ]. Furthermore, MEF2C and NFAT4 expression were reduced, suggesting that an increased expression of STIM2.1 during myogenesis promotes the formation of myotubes through MEF2C and NFAT4.…”

Section: Variety Of Stim Molecules Expressed In Adult Tissuementioning

confidence: 99%

Store-Operated Calcium Entry in Skeletal Muscle: What Makes It Different?

Lilliu

Koenig

et al. 2021

Cells

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Current knowledge on store-operated Ca2+ entry (SOCE) regarding its localization, kinetics, and regulation is mostly derived from studies performed in non-excitable cells. After a long time of relative disinterest in skeletal muscle SOCE, this mechanism is now recognized as an essential contributor to muscle physiology, as highlighted by the muscle pathologies that are associated with mutations in the SOCE molecules STIM1 and Orai1. This review mainly focuses on the peculiar aspects of skeletal muscle SOCE that differentiate it from its counterpart found in non-excitable cells. This includes questions about SOCE localization and the movement of respective proteins in the highly organized skeletal muscle fibers, as well as the diversity of expressed STIM isoforms and their differential expression between muscle fiber types. The emerging evidence of a phasic SOCE, which is activated during EC coupling, and its physiological implication is described as well. The specific issues related to the use of SOCE modulators in skeletal muscles are discussed. This review highlights the complexity of SOCE activation and its regulation in skeletal muscle, with an emphasis on the most recent findings and the aim to reach a current picture of this mesmerizing phenomenon.

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“…The question we set out to explore was if all of these highly diverse functions of STIM1 are indeed mediated by exactly the same protein, or if and how alternative splicing modifies STIM1 structure and function to adapt to cell-type specific requirements. In the past, we and others have identified a splice variant of STIM2 (STIM2.1; STIM2ß), which prevents interaction and gating of Orai channels 16,17 thus acts as a strong dominant-negative regulator of SOCE by altering the density of activated Orai complexes 18 and has recently been shown to regulate myogenesis by controlling SOCE dependent transcriptional factors 19 . Given the existence of this inhibitory splice variant, the often small effects seen upon genetic deletion of STIM2 may indeed underestimate a STIM2 mediated effect, if the concomitant deletion of expressed STIM2.1 deletes the negative regulator STIM2.1/STIM2ß.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing switches STIM1 targeting to specialized membrane contact sites and modifies SOCE

Knapp

Förderer

Alansary

et al. 2020

Preprint

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Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator molecule of store-operated Ca 2+ entry (SOCE) and a sorting regulator of certain ER proteins such as Stimulator of interferon genes (STING). Here, we characterize a conserved new variant, Stim1A, where splice-insertion translates into an additional C-terminal domain. We find prominent expression of exonA mRNA in testes, astrocytes, kidney and heart and confirm Stim1A protein in Western blot of testes. In situ, endogenous Stim1 with domain A, but not Stim1 without domain A localizes to unique adhesion junctions and to specialized membrane retrieval sites (tubulobulbar complexes) in testes. Functionally, using Ca 2+ imaging and patch-clamp analysis, Stim1A shows a dominant-negative effect on SOCE and I CRAC , despite normal clustering and interaction with Orai1 investigated by combined TIRF and FRET analyses and as confirmed by an increased SOCE upon knock-down of endogenous Stim1A in astrocytes. Mutational analyses in conjunction with imaging and patch-clamp analyses of residues either in domain A or within the N-terminal region of Orai1 demonstrate a specific defect in stabilized channel gating. Our findings demonstrate that celltype specific splicing of STIM1 adds both an intracellular targeting switch and adapts SOCE to meet the Ca 2+ requirements of specific subcellular contact sites. splicing | CRAC | membrane | endocytosis | gating | Sertoli | Orai | calcium | trafficking | variantCorrespondence: barbara.niemeyer@uks.eu

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Orai1 inhibitor STIM2β regulates myogenesis by controlling SOCE dependent transcriptional factors

Cited by 12 publications

References 45 publications

STIM Proteins: An Ever-Expanding Family

STIM Proteins: An Ever-Expanding Family

Store-Operated Calcium Entry in Skeletal Muscle: What Makes It Different?

Alternative splicing switches STIM1 targeting to specialized membrane contact sites and modifies SOCE

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