The STIM-Orai Pathway: STIM-Orai Structures: Isolated and in Complex

Zhu, Jinhui; Feng, Qingping; Stathopulos, Peter B.

doi:10.1007/978-3-319-57732-6_2

Cited by 6 publications

(3 citation statements)

References 91 publications

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“…To date, 18 distinct STIM1 mutations causing TAM have been identified, of which 15 cluster in the EF-hand domains (Morin et al, 2020). According to the resolved STIM1 protein structure (Yang et al, 2012;Zhu et al, 2017;Lopez et al, 2020), TAM-associated STIM1 EF-hand mutations appear to affect amino acids involved in Ca 2+ coordination or forming a hydrophobic pocket which maintains STIM1 in a folded state (Stathopulos et al, 2008;Böhm et al, 2014). Functional impact of TAM-associated STIM1 EF-hand mutations has been investigated through their heterologous expression in murine C2C12 myoblasts (Böhm et al, 2013) as well as in other engineered cell lines (Hedberg et al, 2014;Nesin et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

Conte

Pannunzio

Imbrici

et al. 2021

Front. Cell Dev. Biol.

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Tubular Aggregate Myopathy (TAM) is a hereditary ultra-rare muscle disorder characterized by muscle weakness and cramps or myasthenic features. Biopsies from TAM patients show the presence of tubular aggregates originated from sarcoplasmic reticulum due to altered Ca2+ homeostasis. TAM is caused by gain-of-function mutations in STIM1 or ORAI1, proteins responsible for Store-Operated-Calcium-Entry (SOCE), a pivotal mechanism in Ca2+ signaling. So far there is no cure for TAM and the mechanisms through which STIM1 or ORAI1 gene mutation lead to muscle dysfunction remain to be clarified. It has been established that post-natal myogenesis critically relies on Ca2+ influx through SOCE. To explore how Ca2+ homeostasis dysregulation associated with TAM impacts on muscle differentiation cascade, we here performed a functional characterization of myoblasts and myotubes deriving from patients carrying STIM1 L96V mutation by using fura-2 cytofluorimetry, high content imaging and real-time PCR. We demonstrated a higher resting Ca2+ concentration and an increased SOCE in STIM1 mutant compared with control, together with a compensatory down-regulation of genes involved in Ca2+ handling (RyR1, Atp2a1, Trpc1). Differentiating STIM1 L96V myoblasts persisted in a mononuclear state and the fewer multinucleated myotubes had distinct morphology and geometry of mitochondrial network compared to controls, indicating a defect in the late differentiation phase. The alteration in myogenic pathway was confirmed by gene expression analysis regarding early (Myf5, Mef2D) and late (DMD, Tnnt3) differentiation markers together with mitochondrial markers (IDH3A, OGDH). We provided evidences of mechanisms responsible for a defective myogenesis associated to TAM mutant and validated a reliable cellular model usefull for TAM preclinical studies.

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Section: Introductionmentioning

confidence: 99%

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

Conte

Pannunzio

Imbrici

et al. 2021

Front. Cell Dev. Biol.

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“…IP 3 can then bind to its receptors (IP 3 R) on the ER membrane, favoring the Ca 2+ release to the cytoplasm. In excitable cells, ryanodine receptors (RyR) are reported to play a greater role in luminal ER Ca 2+ depletion than IP 3 R. That said, after the decrease of Ca 2+ stored in the ER, CRACs are activated, providing a sustained influx of Ca 2+ ( Zhu et al, 2017 ).…”

Section: Ion Channels Involved In Asthmamentioning

confidence: 99%

A review of the pathophysiology and the role of ion channels on bronchial asthma

Figueiredo,

Ferreira,

Fernandes

et al. 2023

Front. Pharmacol.

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Asthma is one of the main non-communicable chronic diseases and affects a huge portion of the population. It is a multifactorial disease, classified into several phenotypes, being the allergic the most frequent. The pathophysiological mechanism of asthma involves a Th2-type immune response, with high concentrations of allergen-specific immunoglobulin E, eosinophilia, hyperreactivity and airway remodeling. These mechanisms are orchestrated by intracellular signaling from effector cells, such as lymphocytes and eosinophils. Ion channels play a fundamental role in maintaining the inflammatory response on asthma. In particular, transient receptor potential (TRP), stock-operated Ca2+ channels (SOCs), Ca2+-activated K+ channels (IKCa and BKCa), calcium-activated chloride channel (TMEM16A), cystic fibrosis transmembrane conductance regulator (CFTR), piezo-type mechanosensitive ion channel component 1 (PIEZO1) and purinergic P2X receptor (P2X). The recognition of the participation of these channels in the pathological process of asthma is important, as they become pharmacological targets for the discovery of new drugs and/or pharmacological tools that effectively help the pharmacotherapeutic follow-up of this disease, as well as the more specific mechanisms involved in worsening asthma.

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“…A large number of ion channels bind and are regulated by CaM, either in its Ca 2+ -bound and/or Ca 2+ -free form. This includes the IP 3 and ryanodine receptors (reviewed in [199,200]), ORAI channels (reviewed in [201]), TRP channels (reviewed in [202,203]), ligand-gated Ca 2+ channels (reviewed in [204]), voltage-dependent Ca 2+ channels (reviewed in [205]), voltage-dependent Na + channels (reviewed in [206,207]), voltage-dependent K + channels [208,209], Ca 2+ -activated K + channels (reviewed in [210]), and Ca 2+ -activated Cl − channels (reviewed in [211]). Although in certain cases CaM is constitutively bound to some ion channels and can be considered an intrinsic subunit of the channel [19], it is important to consider whether the CBS of these channels, when free of CaM, could interact with other regions of the same or different subunit of the channel.…”

Section: Perspectivesmentioning

confidence: 99%

Proteins with calmodulin-like domains: structures and functional roles

Villalobo

González‐Muñoz

Berchtold

2019

Cell. Mol. Life Sci.

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The appearance of modular proteins is a widespread phenomenon during the evolution of proteins. The combinatorial arrangement of different functional and/or structural domains within a single polypeptide chain yields a wide variety of activities and regulatory properties to the modular proteins. In this review, we will discuss proteins, that in addition to their catalytic, transport, structure, localization or adaptor functions, also have segments resembling the helix-loop-helix EF-hand motifs found in Ca 2+ -binding proteins, such as calmodulin (CaM). These segments are denoted CaM-like domains (CaM-LDs) and play a regulatory role, making these CaM-like proteins sensitive to Ca 2+ transients within the cell, and hence are able to transduce the Ca 2+ signal leading to specific cellular responses. Importantly, this arrangement allows to this group of proteins direct regulation independent of other Ca 2+ -sensitive sensor/transducer proteins, such as CaM. In addition, this review also covers CaM-binding proteins, in which their CaM-binding site (CBS), in the absence of CaM, is proposed to interact with other segments of the same protein denoted CaM-like binding site (CLBS). CLBS are important regulatory motifs, acting either by keeping these CaM-binding proteins inactive in the absence of CaM, enhancing the stability of protein complexes and/or facilitating their dimerization via CBS/CLBS interaction. The existence of proteins containing CaM-LDs or CLBSs substantially adds to the enormous versatility and complexity of Ca 2+ /CaM signaling. Keywords α-Actinin • Calcineurin • Calpain • Epidermal growth factor receptor • Glycerol-3-phosphate dehydrogenase • NADPH oxidases • Na + /H + exchanger • Plasma membrane Ca 2+ -ATPase • Protein kinases Abbreviations ADF Actin-depolymerizing factor Bak Bcl2-antagonist/killer CAIN Calcium and internalization CaM Calmodulin CaM-BD CaM-binding domain CaMK-II CaM-dependent protein kinase-II CaM-LD CaM-like domain CaN-A Calcineurin A CaN-B Calcineurin B CBS Calmodulin binding site CDK Cyclin-dependent kinase CDPK/CPK CaM-like domain protein kinase/Ca 2+dependent protein kinase c-erbB Cellular erythroblastic leukemia viral oncogene homologue CLBS Calmodulin-like binding site COMP Cartilage oligomeric matrix protein DAPK1 Death-associated protein kinase 1 ER Endoplasmic reticulum ErbB1/2/3/4 Erythroblastic leukemia viral oncogene homologues 1/2/3/4 EGF Epidermal growth factor EGFR EGF receptor EGFR cyt EGFR cytosolic region FRET Fluorescence resonance energy transfer FSH Follicle-stimulating hormone GPDH Glycerol-3-phosphate dehydrogenase IgA/IgG Immunoglobulins A/G IP 3 Inositol-1,4,5-trisphosphate MAPK1 Mitogen-activated protein kinase 1

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The STIM-Orai Pathway: STIM-Orai Structures: Isolated and in Complex

Cited by 6 publications

References 91 publications

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

A review of the pathophysiology and the role of ion channels on bronchial asthma

Proteins with calmodulin-like domains: structures and functional roles

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